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Browse Health
Geneticist, Obstetrician & Gynecologist (OB/GYN)
28 years of experience
Accepting new patients

Credentials

Education ?

Medical School Score Rankings
University of Minnesota, Twin Cities (1984)
  •  
Top 25%

Awards & Distinctions ?

Awards  
One of America's Leading Experts on:
Birth Defects or Abnormalities (Congenital Abnormalities)
Fetal Diseases
Associations
American Board of Medical Genetics
American Board of Obstetrics and Gynecology

Affiliations ?

Dr. Johnson is affiliated with 3 hospitals.

Hospital Affiliations

Score

Rankings

  • Hospital of the University of PA
    3400 Spruce St, Philadelphia, PA 19104
    •  
    Top 25%
  • Children's Hospital of Philadelphia
    Obstetrician & Gynecologist
    324 S 34th St, Philadelphia, PA 19104
    •  
  • PA Hospital of The University of PA Health System
  • Publications & Research

    Dr. Johnson has contributed to 381 publications.
    Title Desired Characteristics of a Potential Oral and Maxillofacial Surgery Practice Associate: a Connecticut Survey Response.
    Date April 2012
    Journal Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons
    Excerpt

    The goal of the survey was to identify the desired characteristics of recently graduated oral surgeons entering private practice in Connecticut and compare these results to a similar study conducted earlier in New Jersey.

    Title High Dimensional Endophenotype Ranking in the Search for Major Depression Risk Genes.
    Date March 2012
    Journal Biological Psychiatry
    Excerpt

    Despite overwhelming evidence that major depression is highly heritable, recent studies have localized only a single depression-related locus reaching genome-wide significance and have yet to identify a causal gene. Focusing on family-based studies of quantitative intermediate phenotypes or endophenotypes, in tandem with studies of unrelated individuals using categorical diagnoses, should improve the likelihood of identifying major depression genes. However, there is currently no empirically derived statistically rigorous method for selecting optimal endophentypes for mental illnesses. Here, we describe the endophenotype ranking value, a new objective index of the genetic utility of endophenotypes for any heritable illness.

    Title Increased Endoplasmic Reticulum Stress in Decidual Tissue from Pregnancies Complicated by Fetal Growth Restriction with and Without Pre-eclampsia.
    Date March 2012
    Journal Placenta
    Excerpt

    Endoplasmic reticulum (ER) stress has been implicated in both pre-eclampsia (PE) and fetal growth restriction (FGR), and is characterised by activation of three signalling branches: 1) PERK-pEIF2α, 2) ATF6 and 3) splicing of XBP1(U) into XBP1(S). To evaluate the contribution of ER stress in the pathogenesis of PE relative to FGR, we compared levels of ER stress markers in decidual tissue from pregnancies complicated by PE and/or FGR.

    Title Continental Shelf-wide Response of a Fish Assemblage to Rapid Warming of the Sea.
    Date February 2012
    Journal Current Biology : Cb
    Excerpt

    Climate change affects marine biological processes from genetic to ecosystem levels [1-3]. Recent warming in the northeast Atlantic [4, 5] has caused distributional shifts in some fish species along latitudinal and depth gradients [6, 7], but such changes, as predicted by climate envelope models [8], may often be prevented because population movement requires availability of suitable habitat. We assessed the full impacts of warming on the commercially important European continental shelf fish assemblage using a data-driven Eulerian (grid-based) approach that accommodates spatial heterogeneity in ecological and environmental conditions. We analyzed local associations of species abundance and community diversity with climatic variables, assessing trends in 172 cells from records of >100 million individuals sampled over 1.2 million km(2) from 1980-2008. We demonstrate responses to warming in 72% of common species, with three times more species increasing in abundance than declining, and find these trends reflected in international commercial landings. Profound reorganization of the relative abundance of species in local communities occurred despite decadal stability in the presence-absence of species. Our analysis highlights the importance of focusing on changes in species abundance in established local communities to assess the full consequences of climate change for commercial fisheries and food security.

    Title Speciation in Red Algae: Members of the Ceramiales As Model Organisms.
    Date December 2011
    Journal Integrative and Comparative Biology
    Excerpt

    Red algae (Rhodophyta) are an ancient group with unusual morphological, biochemical, and life-history features including a complete absence of flagella. Although the red algae present many opportunities for studying speciation, this has rarely been explicitly addressed. Here, we examine an aspect of paternal gene flow by determining fertilization success of female Neosiphonia harveyi (Ceramiales), which retains a morphological record of all successful and unsuccessful female gametes. High fertilization rates were observed except when there were no males at all within the tidepool, or in a submerged marina environment. Small numbers of reproductive males were able to saturate fertilization rates, suggesting that limited availability of sperm may be less significant in red algae than previously thought. In another member of the Ceramiales, Antithamnion, relatively large chromosomes permit karyological identification of polyploids. The Western Pacific species Antithamnion sparsum is closely related to the diploid species Antithamnion defectum, known only from the Eastern Pacific, and appears to have evolved from it. Molecular evidence suggests that A. sparsum is an autopolyploid, and that the European species known as Antithamnion densum is divergent from the A. sparsum/defectum complex.

    Title The 57 Kb Deletion in Cystinosis Patients Extends into Trpv1 Causing Dysregulation of Transcription in Peripheral Blood Mononuclear Cells.
    Date November 2011
    Journal Journal of Medical Genetics
    Excerpt

    Cystinosis is an autosomal recessive disease characterised by the abnormal accumulation of lysosomal cystine. Mutations in the cystinosin gene (CTNS) represent known causes for the disease. The major cystinosis mutation is a 57 kb deletion on human chromosome 17p13 that removes the majority of CTNS and the entire adjacent gene, CARKL/SHPK.

    Title Fetal Myelomeningocele Surgery: Preschool Functional Status Using the Functional Independence Measure for Children (weefim).
    Date November 2011
    Journal Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery
    Excerpt

    To study preschool functional status in children following fetal myelomeningocele (fMMC) surgery.

    Title Photoprotection in Plants Involves a Change in Lutein 1 Binding Domain in the Major Light-harvesting Complex of Photosystem Ii.
    Date October 2011
    Journal The Journal of Biological Chemistry
    Excerpt

    Nonphotochemical quenching (NPQ) is the fundamental process by which plants exposed to high light intensities dissipate the potentially harmful excess energy as heat. Recently, it has been shown that efficient energy dissipation can be induced in the major light-harvesting complexes of photosystem II (LHCII) in the absence of protein-protein interactions. Spectroscopic measurements on these samples (LHCII gels) in the quenched state revealed specific alterations in the absorption and circular dichroism bands assigned to neoxanthin and lutein 1 molecules. In this work, we investigate the changes in conformation of the pigments involved in NPQ using resonance Raman spectroscopy. By selective excitation we show that, as well as the twisting of neoxanthin that has been reported previously, the lutein 1 pigment also undergoes a significant change in conformation when LHCII switches to the energy dissipative state. Selective two-photon excitation of carotenoid (Car) dark states (Car S(1)) performed on LHCII gels shows that the extent of electronic interactions between Car S(1) and chlorophyll states correlates linearly with chlorophyll fluorescence quenching, as observed previously for isolated LHCII (aggregated versus trimeric) and whole plants (with versus without NPQ).

    Title A Low Comt Activity Haplotype is Associated with Recurrent Preeclampsia in a Norwegian Population Cohort (hunt2).
    Date October 2011
    Journal Molecular Human Reproduction
    Excerpt

    The etiology of preeclampsia is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. Although many candidate genes for preeclampsia have been suggested and studied, the specific causative genes still remain to be identified. Catechol-O-methyltransferase (COMT) is an enzyme involved in catecholamine and estrogen degradation and has recently been ascribed a role in development of preeclampsia. In the present study, we have examined the COMT gene by genotyping the functional Val108/158Met polymorphism (rs4680) and an additional single-nucleotide polymorphism, rs6269, predicting COMT activity haplotypes in a large Norwegian case/control cohort (n(cases)= 1135, n(controls)= 2262). A low COMT activity haplotype is associated with recurrent preeclampsia in our cohort. This may support the role of redox-regulated signaling and oxidative stress in preeclampsia pathogenesis as suggested by recent studies in a genetic mouse model. The COMT gene might be a genetic risk factor shared between preeclampsia and cardiovascular diseases.

    Title Acclimation- and Mutation-induced Enhancement of Psbs Levels Affects the Kinetics of Non-photochemical Quenching in Arabidopsis Thaliana.
    Date October 2011
    Journal Planta
    Excerpt

    The efficiency of photosystem II antenna complexes (LHCs) in higher plants must be regulated to avoid potentially damaging overexcitation of the reaction centre in excess light. Regulation is achieved via a feedback mechanism known as non-photochemical quenching (NPQ), triggered the proton gradient (ΔpH) causing heat dissipation within the LHC antenna. ΔpH causes protonation of the LHCs, the PsbS protein and triggers the enzymatic de-epoxidation of the xanthophyll, violaxanthin, to zeaxanthin. A key step in understanding the mechanism is to decipher whether PsbS and zeaxanthin cooperate to promote NPQ. To obtain clues about their respective functions we studied the effects of PsbS and zeaxanthin on the rates of NPQ formation and relaxation in wild-type Arabidopsis leaves and those overexpressing PsbS (L17) or lacking zeaxanthin (npq1). Overexpression of PsbS was found to increase the rate of NPQ formation, as previously reported for zeaxanthin. However, PsbS overexpression also increased the rate of NPQ relaxation, unlike zeaxanthin, which is known decrease the rate. The enhancement of PsbS levels in plants lacking zeaxanthin (npq1) by either acclimation to high light or crossing with L17 plants showed that the effect of PsbS was independent of zeaxanthin. PsbS levels also affected the kinetics of the 535 nm absorption change (ΔA535), which monitors the formation of the conformational state of the LHC antenna associated with NPQ, in an identical way. The antagonistic action of PsbS and zeaxanthin with respect to NPQ and ΔA535 relaxation kinetics suggests that the two molecules have distinct regulatory functions.

    Title Photoprotective Energy Dissipation Involves the Reorganization of Photosystem Ii Light-harvesting Complexes in the Grana Membranes of Spinach Chloroplasts.
    Date September 2011
    Journal The Plant Cell
    Excerpt

    Plants must regulate their use of absorbed light energy on a minute-by-minute basis to maximize the efficiency of photosynthesis and to protect photosystem II (PSII) reaction centers from photooxidative damage. The regulation of light harvesting involves the photoprotective dissipation of excess absorbed light energy in the light-harvesting antenna complexes (LHCs) as heat. Here, we report an investigation into the structural basis of light-harvesting regulation in intact spinach (Spinacia oleracea) chloroplasts using freeze-fracture electron microscopy, combined with laser confocal microscopy employing the fluorescence recovery after photobleaching technique. The results demonstrate that formation of the photoprotective state requires a structural reorganization of the photosynthetic membrane involving dissociation of LHCII from PSII and its aggregation. The structural changes are manifested by a reduced mobility of LHC antenna chlorophyll proteins. It is demonstrated that these changes occur rapidly and reversibly within 5 min of illumination and dark relaxation, are dependent on ΔpH, and are enhanced by the deepoxidation of violaxanthin to zeaxanthin.

    Title Impact of Mode of Delivery on Markers of Perinatal Hemodynamics in Infants with Hypoplastic Left Heart Syndrome.
    Date August 2011
    Journal The Journal of Pediatrics
    Excerpt

    To determine whether the mode of delivery of infants prenatally diagnosed with hypoplastic left heart syndrome (HLHS) affects markers of perinatal hemodynamics.

    Title Cardiac E-learning: Development of a Web-based Implantable Cardioverter Defibrillator Educational System.
    Date August 2011
    Journal Telemedicine Journal and E-health : the Official Journal of the American Telemedicine Association
    Excerpt

    The objective of this study was to design a Web-based implantable cardioverter defibrillator (ICD) module that would allow greater access to learning which could occur at an individual's convenience outside the fast-paced clinical environment.

    Title Restoration of Rapidly Reversible Photoprotective Energy Dissipation in the Absence of Psbs Protein by Enhanced Deltaph.
    Date July 2011
    Journal The Journal of Biological Chemistry
    Excerpt

    Variations in the light environment require higher plants to regulate the light harvesting process. Under high light a mechanism known as non-photochemical quenching (NPQ) is triggered to dissipate excess absorbed light energy within the photosystem II (PSII) antenna as heat, preventing photodamage to the reaction center. The major component of NPQ, known as qE, is rapidly reversible in the dark and dependent upon the transmembrane proton gradient (ΔpH), formed as a result of photosynthetic electron transport. Using diaminodurene and phenazine metasulfate, mediators of cyclic electron flow around photosystem I, to enhance ΔpH, it is demonstrated that rapidly reversible qE-type quenching can be observed in intact chloroplasts from Arabidopsis plants lacking the PsbS protein, previously believed to be indispensible for the process. The qE in chloroplasts lacking PsbS significantly quenched the level of fluorescence when all PSII reaction centers were in the open state (F(o) state), protected PSII reaction centers from photoinhibition, was modulated by zeaxanthin and was accompanied by the qE-typical absorption spectral changes, known as ΔA(535). Titrations of the ΔpH dependence of qE in the absence of PsbS reveal that this protein affects the cooperativity and sensitivity of the photoprotective process to protons. The roles of PsbS and zeaxanthin are discussed in light of their involvement in the control of the proton-antenna association constant, pK, via regulation of the interconnected phenomena of PSII antenna reorganization/aggregation and hydrophobicity.

    Title Paradoxical Effects of the Cannabinoid Cb2 Receptor Agonist Gw405833 on Rat Osteoarthritic Knee Joint Pain.
    Date February 2011
    Journal Osteoarthritis and Cartilage / Oars, Osteoarthritis Research Society
    Excerpt

    The present study examined whether local administration of the cannabinoid-2 (CB(2)) receptor agonist GW405833 could modulate joint nociception in control rat knee joints and in an animal model of osteoarthritis (OA).

    Title Perinatal and Early Surgical Outcome for the Fetus with Hypoplastic Left Heart Syndrome: a 5-year Single Institutional Experience.
    Date February 2011
    Journal Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology
    Excerpt

    To review our experience with the prenatal diagnosis of hypoplastic left heart syndrome (HLHS). Our goal was to establish the benchmark for perinatal and early surgical outcome in the current era, from a center with an aggressive surgical approach and a cohort with a high level of intention-to-treat.

    Title Genetic and Molecular Functional Characterization of Variants Within Tnfsf13b, a Positional Candidate Preeclampsia Susceptibility Gene on 13q.
    Date February 2011
    Journal Plos One
    Excerpt

    Preeclampsia is a serious pregnancy complication, demonstrating a complex pattern of inheritance. The elucidation of genetic liability to preeclampsia remains a major challenge in obstetric medicine. We have adopted a positional cloning approach to identify maternal genetic components, with linkages previously demonstrated to chromosomes 2q, 5q and 13q in an Australian/New Zealand familial cohort. The current study aimed to identify potential functional and structural variants in the positional candidate gene TNFSF13B under the 13q linkage peak and assess their association status with maternal preeclampsia genetic susceptibility.

    Title Partial Correlation Network Analyses to Detect Altered Gene Interactions in Human Disease: Using Preeclampsia As a Model.
    Date February 2011
    Journal Human Genetics
    Excerpt

    Differences in gene expression between cases and controls have been identified for a number of human diseases. However, the underlying mechanisms of transcriptional regulation remain largely unknown. Beyond comparisons of absolute or relative expression levels, disease states may be associated with alterations in the observed correlational patterns among sets of genes. Here we use partial correlation networks aiming to compare the transcriptional co-regulation for 222 genes that are differentially expressed in decidual tissues between preeclampsia (PE) cases and non-PE controls. Partial correlation coefficients (PCCs) have been calculated in cases (N = 37) and controls (N = 58) separately. For all PCCs, we tested if they were significant non-zero in the cases and controls separately. In addition, to examine if a given PCC is different between the cases and controls, we tested if the difference between two PCCs were significant non-zero. In the group with PE cases, only five PCCs were significant (FDR p value ≤ 0.05), of which none were significantly different from the PCCs in the controls. However, in the controls we identified a total of 56 statistically significant PCCs (FDR p value ≤ 0.05), of which 31 were also significantly different (FDR p value ≤ 0.05) from the PCCs in the PE cases. The identified partial correlation networks included genes that are potentially relevant for developing PE, including both known susceptibility genes (EGFL7, HES1) and novel candidate genes (CFH, NADSYN1, DBP, FIGLA). Our results might suggest that disturbed interactions, or higher order relationships between these genes play an important role in developing the disease.

    Title Origin of Absorption Changes Associated with Photoprotective Energy Dissipation in the Absence of Zeaxanthin.
    Date January 2011
    Journal The Journal of Biological Chemistry
    Excerpt

    To prevent photo-oxidative damage to the photosynthetic membrane in strong light, plants dissipate excess absorbed light energy as heat in a mechanism known as non-photochemical quenching (NPQ). NPQ is triggered by the trans-membrane proton gradient (ΔpH), which causes the protonation of the photosystem II light-harvesting antenna (LHCII) and the PsbS protein, as well as the de-epoxidation of the xanthophyll violaxanthin to zeaxanthin. The combination of these factors brings about formation of dissipative pigment interactions that quench the excess energy. The formation of NPQ is associated with certain absorption changes that have been suggested to reflect a conformational change in LHCII brought about by its protonation. The light-minus-dark recovery absorption difference spectrum is characterized by a series of positive and negative bands, the best known of which is ΔA(535). Light-minus-dark recovery resonance Raman difference spectra performed at the wavelength of the absorption change of interest allows identification of the pigment responsible from its unique vibrational signature. Using this technique, the origin of ΔA(535) was previously shown to be a subpopulation of red-shifted zeaxanthin molecules. In the absence of zeaxanthin (and antheraxanthin), a proportion of NPQ remains, and the ΔA(535) change is blue-shifted to 525 nm (ΔA(525)). Using resonance Raman spectroscopy, it is shown that the ΔA(525) absorption change in Arabidopsis leaves lacking zeaxanthin belongs to a red-shifted subpopulation of violaxanthin molecules formed during NPQ. The presence of the same ΔA(535) and ΔA(525) Raman signatures in vitro in aggregated LHCII, containing zeaxanthin and violaxanthin, respectively, leads to a new proposal for the origin of the xanthophyll red shifts associated with NPQ.

    Title A Transcriptional Profile of the Decidua in Preeclampsia.
    Date January 2011
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    We sought to obtain insight into possible mechanisms underlying preeclampsia using genomewide transcriptional profiling in decidua basalis.

    Title The Relationship of Seizure Activity and Chronic Epilepsy in Early Infancy and Short-term Neurodevelopmental Outcome Following Fetal Myelomeningocele Closure.
    Date January 2011
    Journal Neuropediatrics
    Excerpt

    We explored the relationship between seizure activity (SA) and/or chronic epilepsy (CE) and short-term neurodevelopmental outcomes following fetal myelomeningocele (fMMC) surgery. Retrospective databases and a parental questionnaire focusing on common complications of hindbrain herniation associated with MMC were used to determine the incidence of seizures following fMMC surgery. The Bayley Scales of Infant Development II was used to evaluate the neurocognitive outcomes. The available 3-year outcome data were used for analysis. 54 children underwent fMMC closure at our institution between 1998 and 2003. 48 (89%) families participated. The shunt rate was 50% (n=24). Seizures developed in 8/48 (17%) children, 2 (8%) non-shunted and 6 (25%) shunted (P=0.07). Of those six, 3 developed CE. Neurodevelopmental scores in the average range were found in both non-shunted and 3 shunted fMMC children. The remaining 3 shunted toddlers had CE and significant neurodevelopmental delays. Of those, 2 had severe intracranial hemorrhage and one developed frequent apneic spells in combination with epilepsy. The incidence of seizures in fMMC children was similar to previously reported data of postnatally repaired MMC patients. SA alone without CE was not associated with a worse neurocognitive outcome. The occurrence of severe acquired intracranial injury and CE, however, appeared to be correlated with adverse neurocognitive outcome following fMMC surgery.

    Title Bivariate Genetic Association of Kiaa1797 with Heart Rate in American Indians: the Strong Heart Family Study.
    Date December 2010
    Journal Human Molecular Genetics
    Excerpt

    Heart rate (HR) has been identified as a risk factor for cardiovascular disease (CVD), yet little is known regarding genetic factors influencing this phenotype. Previous research in American Indians (AIs) from the Strong Heart Family Study (SHFS) identified a significant quantitative trait locus (QTL) for HR on chromosome 9p21. Genetic association on HR was conducted in the SHFS. HR was measured from electrocardiogram (ECG) and echocardiograph (Echo) Doppler recordings. We examined 2248 single-nucleotide polymorphisms (SNPs) on chromosome 9p21 for association using a gene-centric statistical test. We replicated the aforementioned QTL [logarithm of odds (LOD) = 4.83; genome-wide P= 0.0003] on chromosome 9p21 in one SHFS population using joint linkage of ECG and Echo HR. After correcting for effective number of SNPs using a gene-centric test, six SNPs (rs7875153, rs7848524, rs4446809, rs10964759, rs1125488 and rs7853123) remained significant. We applied a novel bivariate association method, which was a joint test of association of a single locus to two traits using a standard additive genetic model. The SNP, rs7875153, provided the strongest evidence for association (P = 7.14 x 10(-6)). This SNP (rs7875153) is rare (minor allele frequency = 0.02) in AIs and is located within intron 9 of the gene KIAA1797. To support this association, we applied lymphocyte RNA expression data from the San Antonio Family Heart Study, a longitudinal study of CVD in Mexican Americans. Expression levels of KIAA1797 were significantly associated (P = 0.012) with HR. These findings in independent populations support that KIAA1797 genetic variation may be associated with HR but elucidation of a functional relationship requires additional study.

    Title Outcomes in a Cohort of Patients with Stage I Twin-to-twin Transfusion Syndrome.
    Date December 2010
    Journal Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology
    Excerpt

    To determine pregnancy outcomes of patients who present with Stage I twin-to-twin transfusion syndrome (TTTS).

    Title Predicting the Severity of Congenital High Airway Obstruction Syndrome.
    Date December 2010
    Journal Journal of Pediatric Surgery
    Excerpt

    Congenital high airway obstruction syndrome (CHAOS) is caused by complete or near-complete obstruction of the fetal airway. Obstruction sets in motion a sequence of events that can ultimately lead to fetal demise. However, on rare occasions in utero airway decompression occurs, reversing syndromic findings and improving the prognosis. In our relatively large series of CHAOS patients, we have observed a spectrum of clinical severity. The aim of this study was to identify the prenatal characteristics of CHAOS predictive of a milder postnatal course.

    Title Fronts, Jumps and Secondary Introductions Suggested As Different Invasion Patterns in Marine Species, with an Increase in Spread Rates over Time.
    Date December 2010
    Journal Proceedings. Biological Sciences / The Royal Society
    Excerpt

    Not all introduced (invasive) species in a region will spread from a single point of introduction. Long-distance dispersal or further introductions can obscure the pattern of spread, but the regional importance of such processes is difficult to gauge. These difficulties are further compounded when information on the multiple scale process of invasive species range expansion is reduced to one-dimensional estimates of spread (e.g. km yr(-1)). We therefore compared the results of two different metrics of range expansion: maximum linear rate of spread and accumulation of occupied grid squares (50 x 50 km) over time. An analysis of records for 54 species of introduced marine macrophytes in the Mediterranean and northeast Atlantic revealed cases where the invasion process was probably missed (e.g. Atlantic Bonnemaisonia hamifera) and suggested cases of secondary introductions or erratic jump dispersal (Dasysiphonia sp. and Womersleyella setacea). A majority of species analysed showed evidence for an accumulation of invaded sites without a clear invasion front. Estimates of spread rate are increasing for more recent introductions. The increase is greater than can be accounted for by temporally varying search effort and implies a historical increase in vector efficiency and/or a decreased resistance of native communities to invasion.

    Title Xanthophylls As Modulators of Membrane Protein Function.
    Date November 2010
    Journal Archives of Biochemistry and Biophysics
    Excerpt

    This review discusses the structural aspect of the role of photosynthetic antenna xanthophylls. It argues that xanthophyll hydrophobicity/polarity could explain the reason for xanthophyll variety and help to understand their recently emerging function--control of membrane organization and the work of membrane proteins. The structure of a xanthophyll molecule is discussed in relation to other amphiphilic compounds like lipids, detergents, etc. Xanthophyll composition of membrane proteins, the role of their variety in protein function are discussed using as an example for the major light harvesting antenna complex of photosystem II, LHCII, from higher plants. A new empirical parameter, hydrophobicity parameter (H-parameter), has been introduced as an effective measure of the hydrophobicity of the xanthophyll complement of LHCII from different xanthophyll biosynthesis mutants of Arabidopsis. Photosystem II quantum efficiency was found to correlate well with the H-parameter of LHCII xanthophylls. PSII down-regulation by non-photochemical chlorophyll fluorescence quenching, NPQ, had optimum corresponding to the wild-type xanthophyll composition, where lutein occupies intrinsic sites, L1 and L2. Xanthophyll polarity/hydrophobicity alteration by the activity of the xanthophyll cycle explains the allosteric character of NPQ regulation, memory of illumination history and the hysteretic nature of the relationship between the triggering factor, ΔpH, and the energy dissipation process.

    Title The Making of Fetal Surgery.
    Date October 2010
    Journal Prenatal Diagnosis
    Excerpt

    Fetal diagnosis prompts the question for fetal therapy in highly selected cases. Some conditions are suitable for in utero surgical intervention. This paper reviews historically important steps in the development of fetal surgery. The first invasive fetal intervention in 1963 was an intra-uterine blood transfusion. It took another 20 years to understand the pathophysiology of other candidate fetal conditions and to develop safe anaesthetic and surgical techniques before the team at the University of California at San Francisco performed its first urinary diversion through hysterotomy. This procedure would be abandoned as renal and pulmonary function could be just as effectively salvaged by ultrasound-guided insertion of a bladder shunt. Fetoscopy is another method for direct access to the feto-placental unit. It was historically used for fetal visualisation to guide biopsies or for vascular access but was also abandoned following the introduction of high-resolution ultrasound. Miniaturisation revived fetoscopy in the 1990 s, since when it has been successfully used to operate on the placenta and umbilical cord. Today, it is also used in fetuses with congenital diaphragmatic hernia (CDH), in whom lung growth is triggered by percutaneous tracheal occlusion. It can also be used to diagnose and treat urinary obstruction. Many fetal interventions remain investigational but for a number of conditions randomised trials have established the role of in utero surgery, making fetal surgery a clinical reality in a number of fetal therapy programmes. The safety of fetal surgery is such that even non-lethal conditions, such as myelomeningocoele repair, are at this moment considered a potential indication. This, as well as fetal intervention for CDH, is currently being investigated in randomised trials.

    Title Reproductive Outcomes in Subsequent Pregnancies After a Pregnancy Complicated by Open Maternal-fetal Surgery (1996-2007).
    Date September 2010
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    The reproductive and gynecologic outcomes for women after the pregnancy complicated by open maternal-fetal surgery (OMFS) were evaluated.

    Title Visualizing the Mobility and Distribution of Chlorophyll Proteins in Higher Plant Thylakoid Membranes: Effects of Photoinhibition and Protein Phosphorylation.
    Date September 2010
    Journal The Plant Journal : for Cell and Molecular Biology
    Excerpt

    The diffusion of proteins in chloroplast thylakoid membranes is believed to be important for processes including the photosystem-II repair cycle and the regulation of light harvesting. However, to date there is very little direct information on the mobility of thylakoid proteins. We have used fluorescence recovery after photobleaching in a laser-scanning confocal microscope to visualize in real time the exchange of chlorophyll proteins between grana in intact spinach (Spinacia oleracea L.) and Arabidopsis chloroplasts. Most chlorophyll proteins in the grana appear immobile on the 10-min timescale of our measurements. However, a limited population of chlorophyll proteins (accounting for around 15% of chlorophyll fluorescence) can exchange between grana on this timescale. In intact, wild-type chloroplasts this mobile population increases significantly after photoinhibition, consistent with a role for protein diffusion in the photosystem-II repair cycle. No such increase in mobility is seen in isolated grana membranes, or in the Arabidopsis stn8 and stn7 stn8 mutants, which lack the protein kinases required for phosphorylation of photosystem II core proteins and light-harvesting complexes. Furthermore, mobility under low-light conditions is significantly lower in stn8 and stn7 stn8 plants than in wild-type Arabidopsis. The changes in protein mobility correlate with changes in the packing density and size of thylakoid protein complexes, as observed by freeze-fracture electron microscopy. We conclude that protein phosphorylation switches the membrane system to a more fluid state, thus facilitating the photosystem-II repair cycle.

    Title Transcriptomic Epidemiology of Smoking: the Effect of Smoking on Gene Expression in Lymphocytes.
    Date September 2010
    Journal Bmc Medical Genomics
    Excerpt

    This investigation offers insights into system-wide pathological processes induced in response to cigarette smoke exposure by determining its influences at the gene expression level.

    Title The Fetus As Patient.
    Date August 2010
    Journal Anesthesiology
    Title Social Networks and Physician Adoption of Electronic Health Records: Insights from an Empirical Study.
    Date August 2010
    Journal Journal of the American Medical Informatics Association : Jamia
    Excerpt

    To study how social interactions influence physician adoption of an electronic health records (EHR) system.

    Title Preschool Neurodevelopmental Outcome of Children Following Fetal Myelomeningocele Closure.
    Date May 2010
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    We sought to investigate the preschool neurodevelopmental outcomes of children following fetal myelomeningocele (fMMC) surgery.

    Title Arabidopsis Plants Lacking Psbs Protein Possess Photoprotective Energy Dissipation.
    Date May 2010
    Journal The Plant Journal : for Cell and Molecular Biology
    Excerpt

    It is commonly accepted that the photosystem II subunit S protein, PsbS, is required for the dissipation of excess light energy in a process termed 'non-photochemical quenching' (NPQ). This process prevents photo-oxidative damage of photosystem II (PSII) thus avoiding photoinhibition which can decrease plant fitness and productivity. In this study Arabidopsis plants lacking PsbS (the npq4 mutant) were found to possess a competent mechanism of excess energy dissipation that protects against photoinhibitory damage. The process works on a slower timescale, taking about 1 h to reach the same level of NPQ achieved in the wild type in just a few minutes. The NPQ in npq4 was found to display very similar characteristics to the fast NPQ in the wild type. Firstly, it prevented the irreversible light-induced closure of PSII reaction centres. Secondly, it was uncoupler-sensitive, and thus triggered by the DeltapH across the thylakoid membrane. Thirdly, it was accompanied by significant quenching of the fluorescence under conditions when all PSII reaction centres were open (F(o) state)(.) Fourthly, it was accompanied by NPQ-related absorption changes (DeltaA535). Finally, it was modulated by the presence of the xanthophyll cycle carotenoid zeaxanthin. The existence of a mechanism of photoprotective energy dissipation in plants lacking PsbS suggests that this protein plays the role of a kinetic modulator of the energy dissipation process in the PSII light-harvesting antenna, allowing plants to rapidly track fluctuations of light intensity in the environment, and is not the primary cause of NPQ or a direct carrier of the pigment acting as the non-photochemical quencher.

    Title Urban Fitness Centers: Removing Barriers to Promote Exercise in Underserved Communities.
    Date May 2010
    Journal Journal of Health Care for the Poor and Underserved
    Excerpt

    African Americans, women, the elderly, obese people, and those in underserved communities are less likely than others to participate in leisure-time physical activity. Mercy Catholic Medical Center opened two fitness centers in low-income, predominately minority Philadelphia neighborhoods. Obese/overweight women from ethnic minorities living in low-income neighborhoods participated most frequently.

    Title The North American Fetal Therapy Network (naftnet): a New Approach to Collaborative Research in Fetal Diagnosis and Therapy.
    Date April 2010
    Journal Seminars in Fetal & Neonatal Medicine
    Excerpt

    In August 2004, the National Institutes of Health organized a 'Workshop on Fetal Therapy' to develop a plan for the maternal-fetal, surgical, and neonatal evaluation and treatment of pregnancies that might benefit from in-utero therapy. At the completion of the workshop several recommendations were made, foremost of which was the 'formation of a cooperative group of clinical investigators to help set a national agenda for research and clinical progress in the field of fetal therapy'. Somewhat by coincidence, a multidisciplinary 'Fetal Therapy Working Group' that had been formed earlier in the year was well-positioned to accept this national mandate and proposed development of a North American Fetal Therapy Network (NAFTNet) to foster collaborative research between active fetal diagnosis and treatment centers in both the USA and Canada, develop a peer review mechanism for study proposals, explore ways to centralize data collection and study development, and establish an educational agenda for medical professionals and the public as well as training of future leaders in the field. NAFTNet represents a new paradigm and approach to international collaborative research. Early success has resulted in the recognition of the power of collaborative research efforts in studying rare congenital anomalies and intervention strategies to improve outcomes and survivals in such limited populations. By abandoning 'competitive research' for a cooperative, collaborative environment of research partnership, NAFTNet strives to be more responsible and effective in using limited resources and improving care for pregnancies and children born with congenital anomalies.

    Title Fetal Thoracic and Bladder Shunts.
    Date April 2010
    Journal Seminars in Fetal & Neonatal Medicine
    Excerpt

    Congenital obstructive lesions involving the bladder and the lung can lead to serious complications for the newborn. The in-utero placement of a diverting shunt in the fetal bladder or thoracic cavity can decrease the morbidity and mortality associated with these obstructive conditions. This review focuses on the indications for prenatal evaluation, technique, and outcomes for those fetuses with a lower urinary tract obstruction, congenital pleural effusion or macrocystic congenital cystic adenomatoid malformation after placement of a vesicoamniotic or thoracoamniotic shunt.

    Title Molecular Markers of Preterm Labor in the Choriodecidua.
    Date April 2010
    Journal Reproductive Sciences (thousand Oaks, Calif.)
    Excerpt

    Because relevant biochemical changes are known to begin at the choriodecidual interface some weeks before actual clinical onset of labor, we hypothesized that the preterm choriodecidua may display gene and protein expression patterns specific to preterm labor. Transcriptomic (microarray) and proteomic (2-dimensional gel electrophoresis [2DGE]) profiling methodologies were used to compare changes in choriodecidual tissue collected from women who delivered before 35 weeks of gestation following spontaneous preterm labor (n = 12) and gestation-matched nonlaboring controls (n = 7). Additionally, 2DGE was used to compare differences in protein expression during term and preterm labor and to construct a choriodecidual proteome map. Overall, expressed transcripts and proteins indicated active tissue remodeling independent of labor status and an association with inflammatory processes during labor. Spontaneous, infection-induced and abruption-associated preterm deliveries were each defined by distinct transcriptional profiles. Proteins osteoglycin and progesterone receptor component 2 (PGRMC2) were upregulated during term and preterm labor while galectin 1, annexin 3, annexin 5, and protein disulfide isomerase (PDI) were upregulated only during preterm labor, suggesting a probable association with the underlying pathology. Together, these results represent novel data that warrant further investigations to elucidate plausible causal relationships of these molecules with spontaneous preterm delivery.

    Title Genetic Variation at the Fto Locus Influences Rbl2 Gene Expression.
    Date March 2010
    Journal Diabetes
    Excerpt

    Genome-wide association studies that compare the statistical association between thousands of DNA variations and a human trait have detected 958 loci across 127 different diseases and traits. However, these statistical associations only provide evidence for genomic regions likely to harbor a causal gene(s) and do not directly identify such genes. We combined gene variation and expression data in a human cohort to identify causal genes.

    Title The Photosystem Ii Light-harvesting Protein Lhcb3 Affects the Macrostructure of Photosystem Ii and the Rate of State Transitions in Arabidopsis.
    Date March 2010
    Journal The Plant Cell
    Excerpt

    The main trimeric light-harvesting complex of higher plants (LHCII) consists of three different Lhcb proteins (Lhcb1-3). We show that Arabidopsis thaliana T-DNA knockout plants lacking Lhcb3 (koLhcb3) compensate for the lack of Lhcb3 by producing increased amounts of Lhcb1 and Lhcb2. As in wild-type plants, LHCII-photosystem II (PSII) supercomplexes were present in Lhcb3 knockout plants (koLhcb3), and preservation of the LHCII trimers (M trimers) indicates that the Lhcb3 in M trimers has been replaced by Lhcb1 and/or Lhcb2. However, the rotational position of the M LHCII trimer was altered, suggesting that the Lhcb3 subunit affects the macrostructural arrangement of the LHCII antenna. The absence of Lhcb3 did not result in any significant alteration in PSII efficiency or qE type of nonphotochemical quenching, but the rate of transition from State 1 to State 2 was increased in koLhcb3, although the final extent of state transition was unchanged. The level of phosphorylation of LHCII was increased in the koLhcb3 plants compared with wild-type plants in both State 1 and State 2. The relative increase in phosphorylation upon transition from State 1 to State 2 was also significantly higher in koLhcb3. It is suggested that the main function of Lhcb3 is to modulate the rate of state transitions.

    Title Genetic Variation in Parl Influences Mitochondrial Content.
    Date February 2010
    Journal Human Genetics
    Excerpt

    Given their involvement in processes necessary for life, mitochondrial damage and subsequent dysfunction can lead to a wide range of human diseases. Previous studies of both animal models and humans have suggested that presenilins-associated rhomboid-like protein (PARL) is a key regulator of mitochondrial integrity and function, and plays a role in cellular apoptosis. As a surrogate measure of mitochondrial integrity, we previously measured mitochondrial content in a Caucasian population consisting of large extended pedigrees, with results highlighting a substantial genetic component to this trait. To assess the influence of variation in the PARL gene on mitochondrial content, we re-sequenced 6.5 kb of the gene, identifying 16 SNPs and genotyped these in 1,086 Caucasian individuals, distributed across 170 families. Statistical genetic analysis revealed that one promoter variant, T-191C, exhibited significant effects (after correction for multiple testing) on mitochondrial content levels. Comparison of the transcription factor binding characteristics of the T-191C promoter SNP by EMSA indicates preferential binding of nuclear factors to the T allele, suggesting functional variation in PARL expression. These results suggest that genetic variation within PARL influences mitochondrial abundance and integrity.

    Title Prenatal Diagnosis and Postnatal Outcome of Fetal Spinal Defects Without Arnold-chiari Ii Malformation.
    Date February 2010
    Journal Prenatal Diagnosis
    Excerpt

    To determine the prenatal evolution/natural history and postnatal outcome of fetuses diagnosed with a neural tube defect (NTD) lacking the Arnold-Chiari-II malformation (ACM II).

    Title Invited Commentary.
    Date January 2010
    Journal Physical Therapy
    Title The Erap2 Gene is Associated with Preeclampsia in Australian and Norwegian Populations.
    Date January 2010
    Journal Human Genetics
    Excerpt

    Preeclampsia is a heritable pregnancy disorder that presents new onset hypertension and proteinuria. We have previously reported genetic linkage to preeclampsia on chromosomes 2q, 5q and 13q in an Australian/New Zealand (Aust/NZ) familial cohort. This current study centered on identifying the susceptibility gene(s) at the 5q locus. We first prioritized candidate genes using a bioinformatic tool designed for this purpose. We then selected a panel of known SNPs within ten prioritized genes and genotyped them in an extended set of the Aust/NZ families and in a very large, independent Norwegian case/control cohort (1,139 cases, 2,269 controls). In the Aust/NZ cohort we identified evidence of a genetic association for the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene (rs3734016, P (uncorr) = 0.009) and for the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene (rs2549782, P (uncorr) = 0.004). In the Norwegian cohort we identified evidence of a genetic association for ERAP1 (rs34750, P (uncorr) = 0.011) and for ERAP2 (rs17408150, P (uncorr) = 0.009). The ERAP2 SNPs in both cohorts remained statistically significant (rs2549782, P (corr) = 0.018; rs17408150, P (corr) = 0.039) after corrections at an experiment-wide level. The ERAP1 and ERAP2 genes encode enzymes that are reported to play a role in blood pressure regulation and essential hypertension in addition to innate immune and inflammatory responses. Perturbations within vascular, immunological and inflammatory pathways constitute important physiological mechanisms in preeclampsia pathogenesis. We herein report a novel preeclampsia risk locus, ERAP2, in a region of known genetic linkage to this pregnancy-specific disorder.

    Title Sacrococcygeal Teratomas: Prenatal Surveillance, Growth and Pregnancy Outcome.
    Date November 2009
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Prenatal surveillance and growth characteristics are evaluated in a cohort of fetuses with sacrococcygeal teratomas (SCT) as part of risk assessment.

    Title Lower Extremity Neuromotor Function and Short-term Ambulatory Potential Following in Utero Myelomeningocele Surgery.
    Date November 2009
    Journal Fetal Diagnosis and Therapy
    Excerpt

    To evaluate lower extremity neuromotor function (LENF) and short-term ambulatory potential following fetal myelomeningocele (fMMC) closure.

    Title Photoprotective Energy Dissipation in Higher Plants Involves Alteration of the Excited State Energy of the Emitting Chlorophyll(s) in the Light Harvesting Antenna Ii (lhcii).
    Date October 2009
    Journal The Journal of Biological Chemistry
    Excerpt

    Non-photochemical quenching (NPQ), a mechanism of energy dissipation in higher plants protects photosystem II (PSII) reaction centers from damage by excess light. NPQ involves a reduction in the chlorophyll excited state lifetime in the PSII harvesting antenna (LHCII) by a quencher. Yet, little is known about the effect of the quencher on chlorophyll excited state energy and dynamics. Application of picosecond time-resolved fluorescence spectroscopy demonstrated that NPQ involves a red-shift (60 +/- 5 cm(-1)) and slight enhancement of the vibronic satellite of the main PSII lifetime component present in intact chloroplasts. Whereas this fluorescence red-shift was enhanced by the presence of zeaxanthin, it was not dependent upon it. The red-shifted fluorescence of intact chloroplasts in the NPQ state was accompanied by red-shifted chlorophyll a absorption. Nearly identical absorption and fluorescence changes were observed in isolated LHCII complexes quenched in a low detergent media, suggesting that the mechanism of quenching is the same in both systems. In both cases, the extent of the fluorescence red-shift was shown to correlate with the lifetime of a component. The alteration in the energy of the emitting chlorophyll(s) in intact chloroplasts and isolated LHCII was also accompanied by changes in lutein 1 observed in their 77K fluorescence excitation spectra. We suggest that the characteristic red-shifted fluorescence emission reflects an altered environment of the emitting chlorophyll(s) in LHCII brought about by their closer interaction with lutein 1 in the quenching locus.

    Title Fetal Lower Urinary Tract Obstruction.
    Date October 2009
    Journal Clinics in Perinatology
    Excerpt

    The authors present an overview of the prenatal diagnosis, evaluation, contemporary intervention, and antenatal management of lower urinary tract obstruction. They review early experimental models that confirmed the relation between urinary tract obstruction and renal fibrocystic dysplasia and that early in utero relief of the obstruction could prevent irreversible renal injury. Subsequent studies of the electrolyte and protein concentrations in fetal urine from human cases established prognostic threshold values and helped to develop an algorithm to select candidates for antenatal therapy. Although shunting has improved survival, long-term morbidities remain a significant challenge.

    Title When is Fetoscopic Release of Amniotic Bands Indicated? Review of Outcome of Cases Treated in Utero and Selection Criteria for Fetal Surgery.
    Date August 2009
    Journal Prenatal Diagnosis
    Excerpt

    The objectives are to analyze the outcomes of fetal interventions for fetal limb abnormalities associated with amniotic band syndrome (ABS), to compare the outcome with the known natural history, and to establish selection criteria for fetal intervention.

    Title Reversal of Hindbrain Herniation After Maternal-fetal Surgery for Myelomeningocele Subsequently Impacts on Brain Stem Function.
    Date August 2009
    Journal Neuropediatrics
    Excerpt

    The aim of our study was to delineate whether the reversal of hindbrain herniation (HH) following fetal myelomeningocele (fMMC) closure subsequently reduces the incidence and severity of HH-associated brainstem dysfunction (BSD). Prior to the NIH-sponsored Management of Myelomeningocele Study (MOMS) trial, 54 children underwent fMMC closure at our institution. Forty-eight (89%) families participated in a structured survey focusing on HH-associated BSD (e.g., apnea, neurogenic dysphagia [ND], gastro-esophageal reflux disease [GERD], neuro-ophthalmologic disturbances [NOD]). Median age at follow-up was 72 months (range: 46-98). Fifty-percent required shunting. HH-related symptoms were completely absent in 15 (63%) non-shunted and 10 (42%) shunted children (P=0.15). No HH-related death occurred and none developed severe persistent cyanotic apnea. ND was reported in 2 (8%) non-shunted and 9 (38%) shunted infants (P=0.03). Mild GERD (medically managed) developed in 2 (8%) without and 6 (25%) with shunt placement (P=0.24). NOD was found in 6 (25%) and 13 (54%) of non-shunted and shunted children, respectively (P=0.07). The majority of fMMC children developed no or only mild BSD at follow-up. Our data support the hypothesis that neurodevelopmental deficits associated with MMC are at least partially acquired and that reversal of HH following fMMC surgery may help to reduce the incidence and severity of BSD.

    Title Haploidentical in Utero Hematopoietic Cell Transplantation Improves Phenotype and Can Induce Tolerance for Postnatal Same-donor Transplants in the Canine Leukocyte Adhesion Deficiency Model.
    Date July 2009
    Journal Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation
    Excerpt

    In the murine model, in utero hematopoietic cell transplantation (IUHCT) has been shown to achieve low levels of allogeneic chimerism and associated donor-specific tolerance permitting minimal conditioning postnatal hematopoietic stem cell transplantation (HSCT). In this pilot study, we investigated IUHCT in the canine leukocyte adhesion deficiency (CLAD) model. Haploidentical IUHCT resulted in stable low-level donor cell chimerism in all dogs that could be analyzed by sensitive detection methodology (4 of 10) through 18 months of follow-up. In the 2 CLAD recipients, low-level chimerism resulted in amelioration and complete reversal of the CLAD phenotype, respectively. Six recipients of IUHCT (5 carriers and 1 CLAD) subsequently received postnatal HSCT from the same haploidentical prenatal donor after minimal conditioning with busulfan 10 mg/kg. Chimerism in 2 of 5 CLAD carriers that underwent HSCT increased from < 1% pre-HSCT to sustained levels of 35% to 45%. Control animals undergoing postnatal haploidentical HSCT without IUHCT had no detectable donor chimerism. These results demonstrate that haploidentical IUHCT in the CLAD model can result in low-level donor chimerism that can prevent the lethal phenotype in CLAD dogs, and can result in donor-specific tolerance that can facilitate postnatal minimal conditioning HSCT.

    Title Genetic Association of the Activin A Receptor Gene (acvr2a) and Pre-eclampsia.
    Date May 2009
    Journal Molecular Human Reproduction
    Excerpt

    Pre-eclampsia is a common serious disorder of human pregnancy, which is associated with significant maternal and perinatal morbidity and mortality. The suspected aetiology of pre-eclampsia is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. Recently, we reported significant linkage to chromosome 2q22 in 34 Australian/New Zealand (Aust/NZ) pre-eclampsia/eclampsia families, and activin A receptor type IIA (ACVR2A) was identified as a strong positional candidate gene at this locus. In an attempt to identify the putative risk variants, we have now comprehensively re-sequenced the entire coding region of the ACVR2A gene and the conserved non-coding sequences in a subset of 16 individuals from these families. We identified 45 single nucleotide polymorphisms (SNPs), with 9 being novel. These SNPs were genotyped in our total family sample of 480 individuals from 74 Aust/NZ pre-eclampsia families (including the original 34 genome-scanned families). Our best associations between ACVR2A polymorphisms and pre-eclampsia were for rs10497025 (P = 0.025), rs13430086 (P = 0.010) and three novel SNPs: LF004, LF013 and LF020 (all with P = 0.018). After correction for multiple hypothesis testing, none of these associations reached significance (P > 0.05). Based on these data, it remains unclear what role, if any, ACVR2A polymorphisms play in pre-eclampsia risk, at least in these Australian families. However, it would be premature to rule out this gene as significant associations between ACVR2A SNPs and pre-eclampsia have recently been reported in a large Norwegian (HUNT) population sample.

    Title In Utero Meconium Passage in Fetuses and Newborns with Myelomeningocele.
    Date April 2009
    Journal Journal of Neurosurgery. Pediatrics
    Excerpt

    The authors retrospectively investigated whether midgestational fetal myelomeningocele (fMMC) repair alters intrauterine meconium exposure.

    Title Like a Rolling Stone: the Mobility of Maerl (corallinaceae) and the Neutrality of the Associated Assemblages.
    Date April 2009
    Journal Ecology
    Excerpt

    Beds of nonattached coralline algae (maerl or rhodoliths) are widespread and considered relatively species rich. This habitat is generally found in areas where there is chronic physical disturbance such that maerl thalli are frequently moved. Little is known, however, about how natural disturbance regimes affect the species associated with maerl. This study compared the richness, animal abundance, and algal biomass of maerl-associated species over a two-year period in a wave-disturbed bed and a sheltered maerl bed. Changes in associated species over time were assessed for departures from a neutral model in which the dissimilarity between samples reflects random sampling from a common species pool. Algal biomass and species richness at the wave-exposed site and on stabilized maerl at the sheltered site were reduced at times of higher wind speeds. The changes in species richness were not distinguishable from a neutral model, implying that algal species were added at random to the assemblage as the level of disturbance lessened. Results for animal species were more mixed. Although mobile species were less abundant during windy periods at the exposed site, both neutral and non-neutral patterns were evident in the assemblages. Artificial stabilization of maerl had inconsistent effects on the richness of animals but always resulted in more attached algal species. While the results show that the response of a community to disturbance can be neutral, the domain of neutral changes in communities may be relatively small. Alongside non-neutral responses to natural disturbance, artificial stabilization always resulted in an assemblage that was more distinct than would be expected under random sampling from a common pool. Community responses to stabilization treatments did not consistently follow the predictions of the dynamic equilibrium model, the intermediate disturbance model, or a facilitation model. These inconsistencies may reflect site-specific variation in both the disturbance regime and the adjacent habitats that provide source populations for many of the species found associated with maerl.

    Title An Interface-driven Analysis of User Interactions with an Electronic Health Records System.
    Date April 2009
    Journal Journal of the American Medical Informatics Association : Jamia
    Excerpt

    This study sought to investigate user interactions with an electronic health records (EHR) system by uncovering hidden navigational patterns in the EHR usage data automatically recorded as clinicians navigated through the system's software user interface (UI) to perform different clinical tasks.

    Title Macroalgal Introductions by Hull Fouling on Recreational Vessels: Seaweeds and Sailors.
    Date January 2009
    Journal Environmental Management
    Excerpt

    Macroalgal invasions in coastal areas have been a growing concern during the past decade. The present study aimed to assess the role of hull fouling on recreational yachts as a vector for macroalgal introductions. Questionnaire and hull surveys were carried out in marinas in France and Spain. The questionnaires revealed that the majority of yacht owners are aware of seaweed introductions, usually undertake short range journeys, dry dock their boat at least once a year, and use antifouling paints. The hull survey showed that many in-service yachts were completely free of macroalgae. When present, fouling assemblages consisted mainly of one to two macroalgal species. The most commonly found species was the tolerant green seaweed Ulva flexuosa. Most of the other species found are also cosmopolitan and opportunistic. A few nonnative and potentially invasive Ceramiales (Rhodophyta) were found occasionally on in-service yachts. On the basis of the information gathered during interviews of yacht owners in the surveyed area, these occurrences are likely to be uncommon. However they can pose a significant risk of primary or secondary introductions of alien macroalgal species, especially in the light of the increase in yachting activities. With large numbers of recreational yachts and relatively rare occurrences of nonnative species on hulls, comprehensive screening programs do not seem justified or practical. The risks of transferring nonnative species may, however, be minimized by encouraging the behaviors that prevent fouling on hulls and by taking action against neglected boats before they can act as vectors.

    Title Induction of Efficient Energy Dissipation in the Isolated Light-harvesting Complex of Photosystem Ii in the Absence of Protein Aggregation.
    Date December 2008
    Journal The Journal of Biological Chemistry
    Excerpt

    Under excess illumination, the Photosystem II light-harvesting antenna of higher plants has the ability to switch into an efficient photoprotective mode, allowing safe dissipation of excitation energy into heat. In this study, we show induction of the energy dissipation state, monitored by chlorophyll fluorescence quenching, in the isolated major light-harvesting complex (LHCII) incorporated into a solid gel system. Removal of detergent caused strong fluorescence quenching, which was totally reversible. Singlet-singlet annihilation and gel electrophoresis experiments suggested that the quenched complexes were in the trimeric not aggregated state. Both the formation and recovery of this quenching state were inhibited by a cross-linker, implying involvement of conformational changes. Absorption and CD measurements performed on the samples in the quenched state revealed specific alterations in the spectral bands assigned to the red forms of chlorophyll a, neoxanthin, and lutein 1 molecules. The majority of these alterations were similar to those observed during LHCII aggregation. This suggests that not the aggregation process as such but rather an intrinsic conformational transition in the complex is responsible for establishment of quenching. 77 K fluorescence measurements showed red-shifted chlorophyll a fluorescence in the 690-705 nm region, previously observed in aggregated LHCII. The fact that all spectral changes associated with the dissipative mode observed in the gel were different from those of the partially denatured complex strongly argues against the involvement of protein denaturation in the observed quenching. The implications of these findings for proposed mechanisms of energy dissipation in the Photosystem II antenna are discussed.

    Title Social Contagion and Technology Adoption: a Study in Healthcare Professionals.
    Date November 2008
    Journal Amia ... Annual Symposium Proceedings / Amia Symposium. Amia Symposium
    Excerpt

    This study applies social network analysis approach to studying technology adoption behavior by healthcare professionals. The empirical study was conducted in an ambulatory, primary care clinic where users use a clinical decision support system to treat patients. Strong evidence of social contagion is found in the structural equivalence of friendship network, particularly within the segment between residents and their attending physicians. None of the direct communication networks is found to have significant impact on usage.

    Title Kinetic Analysis of Human Enzyme Rdh10 Defines the Characteristics of a Physiologically Relevant Retinol Dehydrogenase.
    Date September 2008
    Journal The Journal of Biological Chemistry
    Excerpt

    Human retinol dehydrogenase 10 (RDH10) was implicated in the oxidation of all-trans-retinol for biosynthesis of all-trans-retinoic acid, however, initial assays suggested that RDH10 prefers NADP(+) as a cofactor, undermining its role as an oxidative enzyme. Here, we present evidence that RDH10 is, in fact, a strictly NAD(+)-dependent enzyme with multisubstrate specificity that recognizes cis-retinols as well as all-trans-retinol as substrates. RDH10 has a relatively high apparent K(m) value for NAD(+) (~100 microm) but the lowest apparent K(m) value for all-trans-retinol (~0.035 microm) among all NAD(+)-dependent retinoid oxidoreductases. Due to its high affinity for all-trans-retinol, RDH10 exhibits a greater rate of retinol oxidation in the presence of cellular retinol-binding protein type I (CRBPI) than human microsomal RoDH4, but like RoDH4, RDH10 does not recognize retinol bound to CRBPI as a substrate. Consistent with its preference for NAD(+), RDH10 functions exclusively in the oxidative direction in the cells, increasing the levels of retinaldehyde and retinoic acid. Targeted small interfering RNA-mediated silencing of endogenous RDH10 or RoDH4 expression in human cells results in a significant decrease in retinoic acid production from retinol, identifying both human enzymes as physiologically relevant retinol dehydrogenases. The dual cis/trans substrate specificity suggests a dual physiological role for RDH10: in the biosynthesis of 11-cis-retinaldehyde for vision as well as the biosynthesis of all-trans-retinoic acid for differentiation and development.

    Title An Animal Model of Emotional Blunting in Schizophrenia.
    Date August 2008
    Journal Plos One
    Excerpt

    Schizophrenia is often associated with emotional blunting--the diminished ability to respond to emotionally salient stimuli--particularly those stimuli representative of negative emotional states, such as fear. This disturbance may stem from dysfunction of the amygdala, a brain region involved in fear processing. The present article describes a novel animal model of emotional blunting in schizophrenia. This model involves interfering with normal fear processing (classical conditioning) in rats by means of acute ketamine administration. We confirm, in a series of experiments comprised of cFos staining, behavioral analysis and neurochemical determinations, that ketamine interferes with the behavioral expression of fear and with normal fear processing in the amygdala and related brain regions. We further show that the atypical antipsychotic drug clozapine, but not the typical antipsychotic haloperidol nor an experimental glutamate receptor 2/3 agonist, inhibits ketamine's effects and retains normal fear processing in the amygdala at a neurochemical level, despite the observation that fear-related behavior is still inhibited due to ketamine administration. Our results suggest that the relative resistance of emotional blunting to drug treatment may be partially due to an inability of conventional therapies to target the multiple anatomical and functional brain systems involved in emotional processing. A conceptual model reconciling our findings in terms of neurochemistry and behavior is postulated and discussed.

    Title Cross-species Replication of a Resistin Mrna Qtl, but Not Qtls for Circulating Levels of Resistin, in Human and Baboon.
    Date July 2008
    Journal Heredity
    Excerpt

    Resistin has been associated with inflammation and risk for cardiovascular disease. We previously reported evidence of a QTL on chromosome 19p13 affecting the abundance of resistin (RETN) mRNA in the omental adipose tissue of baboons (L0D score 3.8). In this study, whole genome transcription levels were assessed in human lymphocyte samples from 1240 adults participating in the San Antonio Family Heart Study, using the Sentrix Human-6 Expression Beadchip. Lymphocytes were surveyed, as it has been proposed that their expression levels may reflect those in harder to ascertain tissues, such as adipose tissue, that are thought to be more directly relevant to disease procesn was conducted to detect loci affecting RETN mRNA levels. We obtained significant evidence for a QTL influencing the RETN expression (LOD score 10.7) on chromosome 19p. This region is orthologous/homologous to the region previously localized on baboon chromosome 19. The strongest positional candidate gene in this region is the structural gene for resistin, itself. We also found evidence for a QTL influencing resistin protein levels (LOD score 5.3) on chromosome 14q. This differs from our previously reported QTL on chromosome 18 in baboons. The different QTLs for circulating protein suggests that post-translational processing and turnover may be influenced by different or multiple genes in baboons and humans. The parallel findings of a cis-eQTL for RETN mRNA in baboon omental tissue and human lymphocytes lends support to the strategy of using lymphocyte gene expression levels as a surrogate for gene expression levels in other tissues.

    Title The Lhcb Protein and Xanthophyll Composition of the Light Harvesting Antenna Controls the Deltaph-dependency of Non-photochemical Quenching in Arabidopsis Thaliana.
    Date July 2008
    Journal Febs Letters
    Excerpt

    Nonphotochemical quenching (NPQ) is the photoprotective dissipation of energy in photosynthetic membranes. The hypothesis that the DeltapH-dependent component of NPQ (qE) component of non-photochemical quenching is controlled allosterically by the xanthophyll cycle has been tested using Arabidopsis mutants with different xanthophyll content and composition of Lhcb proteins. The titration curves of qE against DeltapH were different in chloroplasts containing zeaxanthin or violaxanthin, proving their roles as allosteric activator and inhibitor, respectively. The curves differed in mutants deficient in lutein and specific Lhcb proteins. The results show that qE is determined by xanthophyll occupancy and the structural interactions within the antenna that govern allostericity.

    Title Main Bronchus Occlusion for Treatment of Congenital Diaphragmatic Hernia in Fetal Lambs.
    Date June 2008
    Journal Journal of Pediatric Surgery
    Excerpt

    PURPOSE: The present study investigates a new surgical approach in the treatment of left diaphragmatic hernia in fetal sheep. We postulated that unlike tracheal occlusion where both lungs are occluded, selective left main bronchus occlusion (LMBO) would accelerate growth of only the left lung, reduce left visceral herniation, and recover space in the both thoraces necessary for lung development. METHODS: Left-sided congenital diaphragmatic hernia (CDH) was surgically created in 8 fetal lambs at approximately 65 days of gestation; in 4 of these animals, LMBO was performed at approximately 118 days. Four sham-operated animals served as controls. Lambs were delivered by hysterotomy at 137 days. We measured lung-to-body weight ratios, alveolar surface area, septal wall thickness, and AE2 cell density in the left and right lungs. RESULTS: Left main bronchus occlusion increased (P < .05) left lung growth causing severe right mediastinal shift but failed to reduce herniated abdominal viscera in 3 of 4 lambs. Wet lung-to-body weight ratio in LMBO group was similar to that of the control group; however, this was achieved by overgrowth of left lung, whereas the right wet lung-to-body weight ratio remained low. In the LMBO group, right lung AE2 cell density was higher than that of control group and not different to that of the CDH group. CONCLUSIONS: Left main bronchus occlusion failed to restore normal pulmonary development in CDH.

    Title Prenatal Ultrasonographic Gastrointestinal Abnormalities in Fetuses with Gastroschisis Do Not Correlate with Postnatal Outcomes.
    Date June 2008
    Journal Journal of Pediatric Surgery
    Excerpt

    PURPOSE: In the setting of gastroschisis, the clinical significance of prenatal ultrasound findings of secondary changes in bowel appearance remains unknown. The purpose of this study was to correlate prenatal identification of additional gastrointestinal sonographic abnormalities with postnatal clinical outcome. METHODS: A retrospective review was conducted on 64 fetuses with a prenatal diagnosis of gastroschisis treated at the Children's Hospital of Philadelphia from 2000 to 2007. Postnatal outcomes were compared between newborns with additional sonographic gastrointestinal abnormalities and those without secondary changes to the bowel appearance. RESULTS: Thirty (47%) patients had at least one gastrointestinal abnormality (eg, bowel dilatation, echogenic bowel, thickened bowel, matted bowel, herniation of the stomach through the abdominal wall defect, or segmental loss of bowel peristalsis) on prenatal ultrasound. There were no significant differences between groups with respect to the time to initial and full enteral nutrition, total hospital stay, requirement for ventilator support, central line infection rates, reoperation rates, or mortality. CONCLUSIONS: In the setting of gastroschisis, isolated findings of gastrointestinal abnormalities on prenatal ultrasound do not correlate with adverse postnatal outcome.

    Title Oeis Sequence--a Rare Congenital Anomaly with Prenatal Evaluation and Postnatal Outcome in Six Cases.
    Date May 2008
    Journal Prenatal Diagnosis
    Excerpt

    OBJECTIVE: To describe the outcome of children prenatally diagnosed with omphalocele, exstrophy of the cloaca, imperforate anus and spinal defects (OEIS). METHOD: A retrospective study identified six fetuses diagnosed with OEIS from 2001 to 2007 and data were collected from pre- and postnatal charts. RESULTS: Prenatal findings included an infraumbilical wall defect, omphalocele, no visible bladder and spinal defects. Abnormalities of the upper urinary tract were seen in all cases and ambiguous genitalia in four. Four women continued the pregnancy after prenatal counseling and these fetuses were liveborn at a mean gestational age of 36 weeks. Postnatal evaluation confirmed the prenatal findings in the neonates. The children have required multiple surgeries. Common complications are recurrent urinary tract infections and failure to thrive. Neurodevelopment and motor function are normal in all children, except for one child with lower extremity paralysis and global developmental delay. CONCLUSION: Prenatal diagnosis of OEIS is reliable and no significant differences in pre- and postnatal findings in the children were found. Correct diagnosis of abnormalities of external and internal genitalia remains a challenge and abnormalities of the upper urinary tract are common. Postnatal survival is good but associated with considerable morbidity and psychosocial consequences.

    Title Outcomes After Postnatal Resection of Prenatally Diagnosed Asymptomatic Cystic Lung Lesions.
    Date May 2008
    Journal Journal of Pediatric Surgery
    Excerpt

    BACKGROUND: Symptomatic congenital lung lesions require surgical resection, but the management of asymptomatic lung lesions is controversial. Some surgeons advocate observation because of concerns about potential operative morbidity and mortality, as well as a lack of long-term follow-up information. On the other hand, malignant degeneration, pneumonia, and pneumothorax are known consequences of cystic lung lesions. This study aims to assess the safety of resection for asymptomatic lung lesions that were diagnosed before birth. METHODS: A retrospective review of all patients with prenatally diagnosed lung lesions at Children's Hospital of Philadelphia (Philadelphia, Penn) was performed from 1996 to 2005. The perioperative course of patients who were asymptomatic was analyzed. RESULTS: One hundred five complete records of children with asymptomatic lesions were reviewed. Overall mortality was 0% and morbidity was 6.7% including 2.9% significant postoperative air leak and 3.8% transfusion requirement. Nine patients had a pathologic diagnosis that differed from preoperative radiological findings, and 9 patients had additional pathologic findings. CONCLUSION: This series demonstrates that surgery can be performed safely on patients who were asymptomatic with congenital cystic adenomatoid malformation of the lung and other types of lung lesions with no mortality and minimal morbidity. The frequency of disparate pathologic diagnoses and the potential for development of malignancy and other complications support the argument for early resection.

    Title Photosynthetic Acclimation: Does the Dynamic Structure and Macro-organisation of Photosystem Ii in Higher Plant Grana Membranes Regulate Light Harvesting States?
    Date May 2008
    Journal The Febs Journal
    Excerpt

    The efficiency of light harvesting in higher plant photosynthesis is regulated in response to external environmental conditions. Under conditions of excess light, the normally highly efficient light-harvesting system of photosystem II is switched into a state in which unwanted, potentially harmful, energy is dissipated as heat. This process, known as nonphotochemical quenching, occurs by the creation of energy quenchers following conformational change in the light-harvesting complexes, which is initiated by the build up of the thylakoid pH gradient and controlled by the xanthophyll cycle. In the present study, the evidence to support the notion that this regulatory mechanism is dependent upon the organization of the different antenna subunits in the stacked grana membranes is reviewed. We postulate that nonphotochemical quenching occurs within a structural locus comprising the PsbS subunit and components of the light-harvesting antenna, CP26, CP24, CP29 and LHCIIb (the major trimeric light-harvesting complex), formed in response to protonation and controlled by the xanthophyll cycle carotenoids.

    Title Pregnancy Outcomes Following Bipolar Umbilical Cord Cauterization for Selective Termination in Complicated Monochorionic Multiple Gestations.
    Date April 2008
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To review pregnancy and childhood outcomes following selective termination by ultrasound guided bipolar umbilical cord cauterization (UCC) in complicated monochorionic multifetal pregnancies. STUDY DESIGN: Consenting patients (27 of 49, 55%) had review of pregnancy history and pediatric development in the surviving twin following selective UCC. Results: UCC was performed at 21.2 +/- 2.8 weeks gestational age, followed by a liveborn delivery (n = 28) at 34.4 +/- 4.7 weeks. Mean birth weight was 2,218 +/- 926 g. Complications included preterm labor (25.0%), premature rupture of membranes (17.8%), placental abruption (10.7%) and chorioamnionitis (7.1%). Perinatal mortality was 10.3% in continuing fetuses. However, 96.2% of pregnancies achieved livebirths with 96% of neonates showing apparently normal development between ages 1.5 and 5 years. CONCLUSION: Bipolar UCC is a reasonably safe and effective treatment for selective termination in complicated monochorionic pregnancies.

    Title Classification of Broadband Echoes from Prey of a Foraging Blainville's Beaked Whale.
    Date April 2008
    Journal The Journal of the Acoustical Society of America
    Excerpt

    Blainville's beaked whales (Mesoplodon densirostris) use broadband, ultrasonic echolocation signals with a -10 dB bandwidth from 26 to 51 kHz to search for, localize, and approach prey that generally consist of mid-water and deep-water fishes and squid. Although it is well known that the spectral characteristics of broadband echoes from marine organisms vary as a function of size, shape, orientation, and anatomical group, there is little evidence as to whether or not free-ranging toothed whales use spectral cues in discriminating between prey and nonprey. In order to study the prey-classification process, a stereo acoustic tag was deployed on a Blainville's beaked whale so that emitted clicks and the corresponding echoes from targets in the water could be recorded. A comparison of echoes from targets apparently selected by the whale and those from a sample of scatterers that were not selected suggests that spectral features of the echoes, target strengths, or both may have been used by the whale to discriminate between echoes. Specifically, the whale appears to favor targets with one or more nulls in the echo spectra and to seek prey with higher target strengths at deeper depths.

    Title Genetic Association of Preeclampsia to the Inflammatory Response Gene Seps1.
    Date April 2008
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: The objective of the study was to test for a genetic association between the G-105A promoter polymorphism of the inflammatory mediator Selenoprotein S (SEPS1) and preeclampsia. STUDY DESIGN: A retrospective study in a large Norwegian case-control cohort compared maternal genotype and allele frequencies of the SEPS1 g.-105G>A polymorphism genotyped by SNPlex assay in preeclamptic (n = 1139) and control (n = 2269) women. Statistical significance was determined by chi2 and multivariate regression analyses. RESULTS: Women with preeclampsia were 1.34 times more likely to have the GA or AA genotype (P = .0039; 95% confidence interval [CI] 1.09 to 1.64) and 1.22 times more likely to carry the A allele (P = .023; odds ratio, 1.22; 95% CI, 1.02 to 1.46). CONCLUSION: The A allele of the SEPS1-105G>A polymorphism is a significant risk factor for preeclampsia in this population.

    Title The Xanthophyll Cycle Pool Size Controls the Kinetics of Non-photochemical Quenching in Arabidopsis Thaliana.
    Date March 2008
    Journal Febs Letters
    Excerpt

    Arabidopsis plants overexpressing beta-carotene hydroxylase 1 accumulate over double the amount of zeaxanthin present in wild-type plants. The final amplitude of non-photochemical quenching (NPQ) was found to be the same in these plants, but the kinetics were different. The formation and relaxation of NPQ consistently correlated with the de-epoxidation state of the xanthophyll cycle pool and not the amount of zeaxanthin. These data indicate that zeaxanthin and violaxanthin antagonistically regulate the switch between the light harvesting and photoprotective modes of the light harvesting system and show that control of the xanthophyll cycle pool size is necessary to optimize the kinetics of NPQ.

    Title Prenatally Diagnosed Fetal Lung Lesions with Associated Conotruncal Heart Defects: is There a Genetic Association?
    Date March 2008
    Journal Prenatal Diagnosis
    Excerpt

    Congenital lung malformation can easily be diagnosed by prenatal ultrasound. Associated extrapulmonary malformations such as heart defects and chromosomal aberrations are rare.OBJECTIVE: The objective of this study was to describe the natural history, outcome and other associated malformations in fetuses with lung lesions and an associated heart defect. METHODS: Retrospective analysis of 4 cases of prenatally diagnosed fetal CCAMs and hybrid lesions with an associated heart defect and review of 8 cases in the literature. RESULTS: At a single referral center 1.9% of the fetuses with Congenital cystic adenomatoid malformation (CCAM) were diagnosed with an associated heart defect. Seven of the total 12 cases (58%) reviewed had a conotruncal heart abnormality. Chromosomal abnormalities were found in 5 (42%) of the cases. CONCLUSION: This retrospective review shows that karyotyping in fetal lung lesions with an associated heart defect or isolated large lung lesions is indicated. It also suggests that there is a subpopulation of fetuses with CCAMs who have conotruncal heart defects. This finding may suggest a common genetic background.

    Title Antenatal Diagnosis and Management of Congenital Cystic Adenomatoid Malformation.
    Date February 2008
    Journal Seminars in Fetal & Neonatal Medicine
    Excerpt

    One of the most enigmatic pulmonary lesions encountered in the prenatal period is the congenital cystic adenomatoid malformation (CCAM). This review presence current thinking on pathogenesis, prenatal assessment, fetal intervention, and management for this pulmonary malformation. Careful delivery planning by utilizing a multidisciplinary approach will optimize neonatal outcomes.

    Title Discovery of Expression Qtls Using Large-scale Transcriptional Profiling in Human Lymphocytes.
    Date January 2008
    Journal Nature Genetics
    Excerpt

    Quantitative differences in gene expression are thought to contribute to phenotypic differences between individuals. We generated genome-wide transcriptional profiles of lymphocyte samples from 1,240 participants in the San Antonio Family Heart Study. The expression levels of 85% of the 19,648 detected autosomal transcripts were significantly heritable. Linkage analysis uncovered >1,000 cis-regulated transcripts at a false discovery rate of 5% and showed that the expression quantitative trait loci with the most significant linkage evidence are often located at the structural locus of a given transcript. To highlight the usefulness of this much-enlarged map of cis-regulated transcripts for the discovery of genes that influence complex traits in humans, as an example we selected high-density lipoprotein cholesterol concentration as a phenotype of clinical importance, and identified the cis-regulated vanin 1 (VNN1) gene as harboring sequence variants that influence high-density lipoprotein cholesterol concentrations.

    Title Postnatal Chest Wall Deformities After Fetal Thoracoamniotic Shunting for Congenital Cystic Adenomatoid Malformation.
    Date December 2007
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVES: Large macrocystic congenital cystic adenomatoid malformations (CCAMs) can be treated with thoracoamniotic (TA) shunting to reduce CCAM volume. Two CCAM fetuses treated with TA shunt had postnatal radiographic rib deformities. STUDY DESIGN: Retrospective review of prenatal TA shunting for large macrocystic CCAMs evaluated for the presence of rib deformities. Comparison groups not eligible for TA shunting included nonshunted CCAMs resected postnatally (group A) and size-matched nonshunted CCAMs resected postnatally (group B). RESULTS: Chest wall abnormalities were identified in 77% of newborns ranging from severe concavity and fractures (in two fetuses shunted at 18 and 20 weeks of gestation) to rib thinning compared to comparison groups A and B. The severity of chest wall deformity correlated with earlier gestational age at shunting. CONCLUSIONS: TA shunting at less than 21 weeks of gestational age may result in postnatal chest wall deformity. This observation should be discussed during counseling for this procedure.

    Title The Twin-twin Transfusion Syndrome: Spectrum of Cardiovascular Abnormality and Development of a Cardiovascular Score to Assess Severity of Disease.
    Date November 2007
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Current means of grading twin-twin transfusion syndrome does not characterize cardiovascular aspects adequately. We sought to develop a score that describes the magnitude of cardiovascular severity in twin-twin transfusion syndrome. STUDY DESIGN: Fetal echocardiograms of 150 monochorionic/diamniotic twins were reviewed. Blinded to Quintero stage, we applied a cardiovascular score to each twin set and compared it to the Quintero grade. The score is a composite of variables that include ventricular hypertrophy, dilation, function, valve regurgitation, great artery size, and diastolic properties in the recipient and umbilical artery flow in the donor. Doppler indices of vascular and ventricular function were measured. RESULTS: Mean age was 21 +/- 3 weeks. Discrepancy was noted in degree of severity between Quintero and cardiovascular stages. The score correlated well with myocardial performance index of the recipient right ventricle (r2 = .65). CONCLUSION: We describe the spectrum of cardiovascular abnormalities that are seen in twin-twin transfusion syndrome and propose a scoring system for assessment of severity.

    Title Liver Position and Lung-to-head Ratio for Prediction of Extracorporeal Membrane Oxygenation and Survival in Isolated Left Congenital Diaphragmatic Hernia.
    Date November 2007
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: The purpose of this study was to determine the ability of liver position and lung-to-head ratio to predict outcome in isolated left congenital diaphragmatic hernia. STUDY DESIGN: We reviewed prenatal studies and postnatal outcomes of congenital diaphragmatic hernia between January 1996 and January 2006. RESULTS: Eighty-nine patients received prenatal and postnatal care at 1 institution. In fetuses with liver up, extracorporeal membrane oxygenation was required in 39 of 49 fetuses (80%), compared with 10 of 40 fetuses (25%) for those with liver down (P < .0001). Overall survival rate was 45%, compared with 93% for those with liver down (P < .00005). Low lung-to-head ratio (<1.0) predicted increased incidence of extracorporeal membrane oxygenation (75%; P = .036) and lower survival (35%; P = .0003). However, when measured at <24 weeks of gestation, lung-to-head ratio was not predictive of outcome (extracorporeal membrane oxygenation, P = .108; survival, P = .150); liver position remained highly predictive (extracorporeal membrane oxygenation, P = .006; survival, P = .001). CONCLUSION: Liver position is the best prenatal predictor of outcome in isolated left congenital diaphragmatic hernia. Lung-to-head ratio alone should not be used to counsel families regarding mid gestational management choices.

    Title Genetic Determinants of Mitochondrial Content.
    Date November 2007
    Journal Human Molecular Genetics
    Excerpt

    The mitochondria are the major cellular site of energy production and respiration. Recent research has focused on investigating the role of mitochondria in disease development and it has become increasingly evident that mitochondrial dysfunction contributes to a variety of human diseases. Mitochondrial DNA (mtDNA) quantity is very important for maintaining mitochondrial function and meeting the energy needs of the body. We have measured mitochondrial content in 1259 Mexican American individuals (from 42 extended families) and have shown that mtDNA quantity (a surrogate measure of mitochondrial integrity) has a large genetic component. We performed a genome scan and a genome-wide quantitative transcriptomic scan to identify QTLs influencing mitochondrial content. A variance components linkage-based genome scan utilizing 439 STR markers was used to localize a QTL for mitochondrial content on chromosome 10q (LOD = 3.83). Significant linkage to the mitochondrial genome was also detected for mitochondrial transmission (LOD = 3.39). For replication, we measured mitochondrial content in an independent Caucasian population (1088 individuals) finding evidence for linkage in these same regions. As part of the San Antonio Family Heart Study, we obtained genome-wide quantitative transcriptional profiles from 1240 individuals. Using lymphocyte samples, we quantitated 20 413 transcripts and examined correlations between the expression levels of these transcripts and mitochondrial content using the variance components method. Using regression analysis allowing for residual genetic components, we identified 829 transcripts (including many novel genes) influencing mitochondrial content that vary in their general biological actions, from cell signaling to cell trafficking and ion binding.

    Title User Interface Optimization for an Electronic Medical Record System.
    Date November 2007
    Journal Studies in Health Technology and Informatics
    Excerpt

    Many information technology-enabled healthcare applications have failed because their interfaces are difficult to use. Unfortunately, little attention has been paid in the health informatics community to designing effective user interfaces that are acceptable to healthcare professionals. This paper illustrates a method for improving application interface usability by applying sequential pattern analysis to analyze temporal event sequences recorded in an electronic medical record system. Such event sequences, or clickstreams, reflect clinicians' navigation patterns in their everyday interactions with the computer system. The identified patterns have been used by software developers to calibrate the user interface of the system, so that the within-application workflow is better aligned with clinicians' mental model of medical problem-solving. Such inferred patterns may also help to modify clinicians' suboptimal practice behavior components, as manifested through their actual usage of this point-of-care electronic system.

    Title 'megapclicks': Acoustic Click Trains and Buzzes Produced During Night-time Foraging of Humpback Whales (megaptera Novaeangliae).
    Date October 2007
    Journal Biology Letters
    Excerpt

    Humpback whales (Megaptera novaeangliae) exhibit a variety of foraging behaviours, but neither they nor any baleen whale are known to produce broadband clicks in association with feeding, as do many odontocetes. We recorded underwater behaviour of humpback whales in a northwest Atlantic feeding area using suction-cup attached, multi-sensor, acoustic tags (DTAGs). Here we describe the first recordings of click production associated with underwater lunges from baleen whales. Recordings of over 34000 'megapclicks' from two whales indicated relatively low received levels at the tag (between 143 and 154dB re 1 microPa pp), most energy below 2kHz, and interclick intervals often decreasing towards the end of click trains to form a buzz. All clicks were recorded during night-time hours. Sharp body rolls also occurred at the end of click bouts containing buzzes, suggesting feeding events. This acoustic behaviour seems to form part of a night-time feeding tactic for humpbacks and also expands the known acoustic repertoire of baleen whales in general.

    Title A Chromosome 11q Quantitative-trait Locus Influences Change of Blood-pressure Measurements over Time in Mexican Americans of the San Antonio Family Heart Study.
    Date October 2007
    Journal American Journal of Human Genetics
    Excerpt

    Although previous genome scans have searched for quantitative-trait loci (QTLs) influencing variation in blood pressure (BP), few have investigated the rate of change in BP over time as a phenotype. Here, we compare results from genomewide scans to localize QTLs for systolic, diastolic, and mean arterial BPs (SBP, DBP, and MBP, respectively) and for rates of change in systolic, diastolic, and mean arterial BPs (rSBP, rDBP, and rMBP, respectively), with use of the longitudinal data collected about Mexican Americans of the San Antonio Family Heart Study (SAFHS). Significant evidence of linkage was found for rSBP (LOD 4.15) and for rMBP (LOD 3.94) near marker D11S4464 located on chromosome 11q24.1. This same chromosome 11q region also shows suggestive linkage to SBP (LOD 2.23) and MBP (LOD 2.37) measurements collected during the second clinic visit. Suggestive evidence of linkage to chromosome 5 was also found for rMBP, to chromosome 16 for rSBP, and to chromosomes 1, 5, 6, 7, and 21 for the single-time-point BP traits collected at the first two SAFHS clinic visits. We also present results from fine mapping the chromosome 11 QTL with use of SNP-association analysis within candidate genes identified from a bioinformatic search of the region and from whole-genome transcriptional expression data collected from 1,240 SAFHS participants. Our results show that the use of longitudinal BP data to calculate the rate of change in BP over time provides more information than do the single-time measurements, since they reveal physiological trends in the subjects that a single-time measurement could never capture. Further investigation of this region is necessary for the identification of the genetic variation responsible for QTLs influencing the rate of change in BP.

    Title Does a Myelomeningocele Sac Compared to No Sac Result in Decreased Postnatal Leg Function Following Maternal Fetal Surgery for Spina Bifida Aperta?
    Date September 2007
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: A fetus with large sac S1 myelomeningocele (MMC) but bilateral talipes prompted the question, 'Does the presence or size of an MMC sac affect postnatal leg function?' STUDY DESIGN: An MMC database with prenatal, birth, and a minimum of 1-year follow-up evaluation was reviewed. All fetuses had in-utero MMC repair at 20 + 0 to 25 + 6 weeks at a single institution. Fifty-four fetuses had prenatal evaluation, with 48 children completing a birth and a 1-year evaluation of leg function. RESULTS: An MMC sac was present in 38/54 (70%) of fetuses evaluated in-utero and had been present in 35/48 (73%) of children evaluated at 1 year of age. Although leg function evaluated at 1 year was better than expected in the 'no sac' group (p = 0.059), this did not reach statistical significance. CONCLUSION: The presence of an MMC sac may increase postnatal lower limb morbidity.

    Title Gastroschisis: Growth Patterns and a Proposed Prenatal Surveillance Protocol.
    Date September 2007
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To assess intrauterine growth for fetuses with gastroschisis using retrospective serial ultrasound assessment from fetuses diagnosed prenatally with gastroschisis. The growth assessment could be available as a prospective tool to direct an antepartum fetal surveillance protocol. METHODS: This is a retrospective review of all cases of gastroschisis evaluated prenatally at a single institution between February 1996 and March 2002. Charts were reviewed for serial ultrasound assessment, gestational age at delivery, mode of delivery, and birth weight. Growth assessment was determined for abdominal circumference, biparietal diameter, head circumference, femur length, and estimated fetal weight (IRB No. 2002-1-2648). RESULTS: Forty patients had delivered by March 2002. One hundred and two ultrasound reports were reviewed. Gastroschisis growth curves showed that the 50th percentile was shifted to the right when compared to normal growth curves for abdominal circumference, biparietal diameter, head circumference, and femur length. The average birth weight was 2,359 g. Compared with a standard population, 44% (16/36) were below the 5th percentile, 61% (22/36) were below the 10th percentile, and 95% (34/36) were below the 50th percentile for gestational age. The average gestational age at delivery was 36.3 weeks. Mothers were nulliparous in 78%, with a mean age of 21.3 years. CONCLUSIONS: (1) Fetuses with gastroschisis show a symmetric intrauterine growth restriction pattern consistent with early development of growth delay; (2) the 50th percentile biometry measurements for the gastroschisis population are shifted to the right on normal fetal growth curves; (3) the birth weight is at or below the 10th percentile in 61% of the newborns with gastroschisis, and (4) an antepartum surveillance protocol is proposed based on growth patterns of fetuses with gastroschisis.

    Title Effect of Maternal Betamethasone Administration on Prenatal Congenital Cystic Adenomatoid Malformation Growth and Fetal Survival.
    Date September 2007
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To evaluate the effect of prenatal steroid treatment on the growth of congenital cystic adenomatoid malformations (CCAM) and survival in affected fetuses not amenable to other percutaneous ultrasound-guided prenatal interventions. METHODS: A retrospective review of patients with a CCAM or hybrid lesion treated with two maternal prenatal betamethasone injections was performed. Patients receiving cyst aspiration or thoracoamniotic shunting at the time of or after steroid administration were excluded. Growth rates and survival data were compared to historical non-steroid treated controls. RESULTS: Eleven patients were treated with prenatal steroids (10 microcystic and 1 macrocystic). Survival was 100% in fetuses with hydrops (5/5) or a CCAM volume ratio (CVR) >1.6 (7/7) at the time of steroid administration. This compares to a mortality of 100 and 56.2% respectively in historical non-treated controls. Resolution of hydrops was seen in 80% (4/5) of steroid-treated patients. CCAM growth rates were variable after steroid administration. However, when compared to historical data where CVR and CCAM volume have been documented to increase until 28 weeks' gestation, the CVR and CCAM volume growth rates decreased in 72.73% and 50% of patients respectively from the time of steroid administration to 28 weeks' gestation. CONCLUSIONS: In the fetus with a CCAM, the presence of hydrops fetalis or a CVR >1.6 is indicative of poor fetal outcome without prenatal intervention. The observed effect of antenatal steroid treatment on CCAM growth is variable, but its potential to improve survival in these high-risk groups is encouraging and warrants further controlled evaluations.

    Title Elevated Zeaxanthin Bound to Oligomeric Lhcii Enhances the Resistance of Arabidopsis to Photooxidative Stress by a Lipid-protective, Antioxidant Mechanism.
    Date September 2007
    Journal The Journal of Biological Chemistry
    Excerpt

    The xanthophyll cycle has a major role in protecting plants from photooxidative stress, although the mechanism of its action is unclear. Here, we have investigated Arabidopsis plants overexpressing a gene encoding beta-carotene hydroxylase, containing nearly three times the amount of xanthophyll cycle carotenoids present in the wild-type. In high light at low temperature wild-type plants exhibited symptoms of severe oxidative stress: lipid peroxidation, chlorophyll bleaching, and photoinhibition. In transformed plants, which accumulate over twice as much zeaxanthin as the wild-type, these symptoms were significantly ameliorated. The capacity of non-photochemical quenching is not significantly different in transformed plants compared with wild-type and therefore an enhancement of this process cannot be the cause of the stress tolerant phenotype. Rather, it is concluded that it results from the antioxidant effect of zeaxanthin. 80-90% of violaxanthin and zeaxanthin in wild-type and transformed plants was localized to an oligomeric LHCII fraction prepared from thylakoid membranes. The binding of these pigments in intact membranes was confirmed by resonance Raman spectroscopy. Based on the structural model of LHCII, we suggest that the protein/lipid interface is the active site for the antioxidant activity of zeaxanthin, which mediates stress tolerance by the protection of bound lipids.

    Title A Pharmacogenomic Evaluation of Migraine Therapy.
    Date September 2007
    Journal Expert Opinion on Pharmacotherapy
    Excerpt

    Migraine is a common idiopathic primary headache disorder with significant mental, physical and social health implications. Accompanying an intense unilateral pulsating head pain other characteristic migraine symptoms include nausea, emesis, phonophobia, photophobia and in approximately 20-30% of migraine cases, neurologic disturbances associated with the aura phase. Although selective serotonin (5-HT) receptor agonists (i.e., 5-HT(1B/1D)) are successful in alleviating migrainous symptoms in < or = 70% of known sufferers, for the remaining 30%, additional migraine abortive medications remain unsuccessful, not tested or yet to be identified. Genetic characterization of the migrainous disorder is making steady progress with an increasing number of genomic susceptibility loci now identified on chromosomes 1q, 4q, 5q, 6p, 11q, 14q, 15q, 17p, 18q, 19p and Xq. The 4q, 5q, 17p and 18q loci involve endophenotypic susceptibility regions for various migrainous symptoms. In an effort to develop individualized pharmacotherapeutics, the identification of these migraine endophenotypic loci may well be the catalyst needed to aid in this goal. In this review the authors discuss the present treatment of migraine, known genomic susceptibility regions and results from migraine (genetic) association studies. The authors also discuss pharmacogenomic considerations for more individualized migraine prophylactic treatments.

    Title Selective Phosphorylation of Antiviral Drugs by Vaccinia Virus Thymidine Kinase.
    Date July 2007
    Journal Antimicrobial Agents and Chemotherapy
    Excerpt

    The antiviral activity of a new series of thymidine analogs was determined against vaccinia virus (VV), cowpox virus (CV), herpes simplex virus, and varicella-zoster virus. Several compounds were identified that had good activity against each of the viruses, including a set of novel 5-substituted deoxyuridine analogs. To investigate the possibility that these drugs might be phosphorylated preferentially by the viral thymidine kinase (TK) homologs, the antiviral activities of these compounds were also assessed using TK-deficient strains of some of these viruses. Some of these compounds were shown to be much less effective in the absence of a functional TK gene in CV, which was unexpected given the high degree of amino acid identity between this enzyme and its cellular homolog. This unanticipated result suggested that the CV TK was important in the mechanism of action of these compounds and also that it might phosphorylate a wider variety of substrates than other type II enzymes. To confirm these data, we expressed the VV TK and human TK1 in bacteria and isolated the purified enzymes. Enzymatic assays demonstrated that the viral TK could efficiently phosphorylate many of these compounds, whereas most of the compounds were very poor substrates for the cellular kinase, TK1. Thus, the specific phosphorylation of these compounds by the viral kinase may be sufficient to explain the TK dependence. This unexpected result suggests that selective phosphorylation by the viral kinase may be a promising new approach in the discovery of highly selective inhibitors of orthopoxvirus replication.

    Title Prospects for Metabotropic Glutamate 1 Receptor Antagonists in the Treatment of Neuropathic Pain.
    Date July 2007
    Journal Journal of Medicinal Chemistry
    Title Identification of Two Novel Quantitative Trait Loci for Pre-eclampsia Susceptibility on Chromosomes 5q and 13q Using a Variance Components-based Linkage Approach.
    Date June 2007
    Journal Molecular Human Reproduction
    Excerpt

    Pre-eclampsia/eclampsia (PE/E) is a common and serious disorder of human pregnancy that is associated with substantial maternal and perinatal morbidity and mortality. The suspected aetiology of PE/E is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. By assuming that the underlying liability towards PE/E susceptibility is inherently quantitative, any PE/E susceptibility gene would represent a quantitative trait locus (QTL). This assumption enables a more refined and powerful variance components procedure using a threshold model for our PE/E statistical analysis. Using this more efficient linkage approach, we have now re-analysed our previously completed Australian/New Zealand genome scan data to identify two novel PE/E susceptibility QTLs on chromosomes 5q and 13q. We have obtained strong evidence of linkage on 5q with a peak logarithm-of-odds (LOD) score of 3.12 between D5S644 and D5S433 [at approximately 121 centimorgan (cM)] and strong evidence of linkage on 13q with a peak LOD score of 3.10 between D13S1265 and D13S173 (at approximately 123 cM). Objective identification and prioritization of positional candidate genes using the quantitative bioinformatics program GeneSniffer revealed highly plausible PE/E candidate genes encoding aminopeptidase enzymes and a placental peptide hormone on the 5q QTL and two type IV collagens on the 13q QTL regions, respectively.

    Title The Impact of Miscarriage on Women's Pregnancy-specific Anxiety and Feelings of Prenatal Maternal-fetal Attachment During the Course of a Subsequent Pregnancy: an Exploratory Follow-up Study.
    Date March 2007
    Journal Journal of Psychosomatic Obstetrics and Gynaecology
    Excerpt

    This study assesses the implications a miscarriage history has on women's pregnancy-specific anxiety and feelings of prenatal maternal-fetal attachment during the 1st and 3rd trimesters of a subsequent pregnancy. Thirty-five pregnant women (N = 10 with a history of miscarriage) volunteered participation completing the Pregnancy Outcome Questionnaire (POQ), the Maternal Antenatal Attachment Scale (MAAS and a demographic/reproductive history questionnaire during the first trimester of pregnancy. Of these, 24 participants completed the measures again during the third trimester of pregnancy. Women with a miscarriage history reported significantly higher pregnancy-specific anxiety at trimester 1 than women with no miscarriage history; even when the effects of parity were controlled. All expectant mothers, irrespective of miscarriage history, scored similarly at trimester 1 on the MAAS scales. By the 3rd trimester, pregnancy-specific anxiety had significantly decreased for women with a miscarriage history whose mean scores on the POQ were now similar to women with no history of miscarriage. Maternal-fetal attachment had significantly risen by the 3rd trimester for all women. These findings suggest that having a miscarriage history may not have a long-lasting adverse effect on woman's psychological adaptation during the course of a subsequent pregnancy.

    Title Congenital Pulmonary Lymphangiectasis Sequence: a Rare, Heterogeneous, and Lethal Etiology for Prenatal Pleural Effusion.
    Date February 2007
    Journal Prenatal Diagnosis
    Excerpt

    OBJECTIVE: Case report and literature review for congenital pulmonary lymphangiectasis (CPL) CASE REPORT: Male fetus with bilateral pleural effusion, thoracoamniotic shunt, preterm delivery, and prolonged neonatal course with neonatal death at 3 months. Autopsy-identified CPL. DISCUSSION: Review of pathology, clinical course, and genetics of CPL. CONCLUSION: This postnatal diagnosis of CPL/Hennekam syndrome must be considered with prenatal counseling regarding a fetus with bilateral pleural effusions. This pathological entity is autosomal recessive and has a significant risk of lethality.

    Title Genotype X Adiposity Interaction Linkage Analyses Reveal a Locus on Chromosome 1 for Lipoprotein-associated Phospholipase A2, a Marker of Inflammation and Oxidative Stress.
    Date February 2007
    Journal American Journal of Human Genetics
    Excerpt

    Because obesity leads to a state of chronic, low-grade inflammation and oxidative stress, we hypothesized that the contribution of genes to variation in a biomarker of these two processes may be influenced by the degree of adiposity. We tested this hypothesis using samples from the San Antonio Family Heart Study that were assayed for activity of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), a marker of inflammation and oxidative stress. Using an approach to model discrete genotypexenvironment (GxE) interaction, we assigned individuals to one of two discrete diagnostic states (or "adiposity environments"): nonobese or obese, according to criteria suggested by the World Health Organization. We found a genomewide maximum LOD of 3.39 at 153 cM on chromosome 1 for Lp-PLA(2). Significant GxE interaction for Lp-PLA(2) at the genomewide maximum (P=1.16 x 10(-4)) was also found. Microarray gene-expression data were analyzed within the 1-LOD interval of the linkage signal on chromosome 1. We found two transcripts--namely, for Fc gamma receptor IIA and heat-shock protein (70 kDa)--that were significantly associated with Lp-PLA(2) (P<.001 for both) and showed evidence of cis-regulation with nominal LOD scores of 2.75 and 13.82, respectively. It would seem that there is a significant genetic response to the adiposity environment in this marker of inflammation and oxidative stress. Additionally, we conclude that GxE interaction analyses can improve our ability to identify and localize quantitative-trait loci.

    Title Conflict and Control: Gender Symmetry and Asymmetry in Domestic Violence.
    Date February 2007
    Journal Violence Against Women
    Excerpt

    Four types of individual partner violence are identified based on the dyadic control context of the violence. In intimate terrorism, the individual is violent and controlling, the partner is not. In violent resistance, the individual is violent but not controlling; the partner is the violent and controlling one. In situational couple violence, although the individual is violent, neither the individual nor the partner is violent and controlling. In mutual violent control, the individual and the partner are violent and controlling. Evidence is presented that situational couple violence dominates in general surveys, intimate terrorism and violent resistance dominate in agency samples, and this is the source of differences across studies with respect to the gender symmetry of partner violence. An argument is made that if we want to understand partner violence, intervene effectively in individual cases, or make useful policy recommendations, we must make these distinctions in our research.

    Title Fetal Head Biometry Assessed by Fetal Magnetic Resonance Imaging Following in Utero Myelomeningocele Repair.
    Date February 2007
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To examine the impact of fetal myelomeningocele (MMC) repair on fetal head biometry and cerebrospinal fluid (CSF) spaces assessed by magnetic resonance imaging (MR) studies. STUDY DESIGN: Axial measurements of intracranial structures were taken at defined anatomical landmarks. Pre- and postnatal head biometry data and CSF spaces obtained from in utero repaired MMC fetuses (n = 22) were compared to the pre- and postnatal measurements of MMC patients that underwent standard neurosurgical MMC repair after birth (n = 16) and a cohort of age-matched control patients (prenatal, n = 52; postnatal, n = 9). RESULTS: In fetuses with MMC, initial MR scans showed an almost complete absence of supratentorial and posterior fossa CSF spaces. No differences in postnatal CSF spaces were found between controls and prenatally repaired MMC newborns. In fetuses with postnatal MMC repair, CSF spaces remained significantly reduced (p < 0.0001). The mean ventricular diameter (VD) increase in the postnatal repaired MMC group was significantly higher compared to the mean percentage of VD increase in the fetal repaired MMC group (6.4 vs. 4.2 mm; p = 0.02). Pre- and postnatal brain thickness measurements were significantly reduced in both MMC populations compared to age-matched normal values (p < 0.0001). In contrast to postnatally repaired patients, in utero repair fetuses showed significant reversal of hindbrain herniation and normalization of the posterior fossa CSF spaces. CONCLUSION: Mid-gestational repair of MMC promotes normalization of extra-axial CSF spaces. Due to progressive ventriculomegaly, brain thickness remains decreased in both prenatal repaired and age-matched non-repaired MMC patients when compared to age-matched normal values. Restoration of CSF volume in the posterior fossa after in utero repair is indicative of reversal of hindbrain herniation.

    Title Prenatal Diagnosis and Postnatal Management of Diffuse Congenital Hyperinsulinism: a Case Report.
    Date January 2007
    Journal Fetal Diagnosis and Therapy
    Excerpt

    We present the first case of the prenatal diagnosis of congenital hyperinsulinism based on the genetic analysis of known family mutations in the SUR1 gene. An amniocentesis was performed at 16 weeks gestation at which time two mutations in the SUR1 gene were identified consistent with the diagnosis of diffuse hyperinsulinism. The mother was transported to our facility and underwent an elective caesarian section at 38 weeks gestation. The diagnosis was confirmed and treatment was initiated within the first minutes of life. After a short course of failed medical management, the patient underwent a 98% pancreatectomy with subsequent good glycemic control. This case highlights the benefits of the timely in utero diagnosis of hyperinsulinism by mutational analysis.

    Title Verbal Labeling As an Assimilation Mnemonic for Abstract Visual Stimuli: the Sample Case of Recognition Memory for Chinese Characters.
    Date November 2006
    Journal Memory & Cognition
    Excerpt

    In four experiments, we examined the effect that presenting a verbal stimulus (viz., an English noun) alongside an abstract visual stimulus (viz., a Chinese character) enhances recognition memory for the abstract visual stimulus. Experiment 1 demonstrated that the character-plus-word combination at both encoding and retrieval results in better recognition than does a character-alone presentation or presenting the combination at encoding only. Experiment 2 demonstrated that presenting the word first and then the character results in better performance than does the opposite order. Experiment 3 showed that the concreteness value of the word, not familiarity, is the critical factor. In Experiment 4, presentation time was varied. More time was needed for liftoff from chance level for the word-character combination than for the character-alone presentation. Together, the results suggest that subjects spontaneously assimilate stimulus and word into a single representation by building asymmetric effortful imagery associations, going from the English word to the Chinese character.

    Title Objective Prioritization of Positional Candidate Genes at a Quantitative Trait Locus for Pre-eclampsia on 2q22.
    Date October 2006
    Journal Molecular Human Reproduction
    Excerpt

    Pre-eclampsia/eclampsia (PE/E) is a common, serious medical disorder of human pregnancy. Familial association of PE/E has been recognized for decades, but the genetics are complex and poorly understood. In an attempt to identify PE/E susceptibility genes, we embarked on a positional cloning strategy using 34 Australian and New Zealand PE/E pedigrees. An initial 10-cM resolution genome scan revealed a putative susceptibility locus spanning a broad region on chromosome 2 that overlaps an independently determined linkage signal seen in Icelandic PE pedigrees. Subsequent fine mapping using 25 additional short tandem repeat (STR) markers in this region and non-parametric multipoint linkage analysis did not change the overall position. Under a strict diagnosis of PE, we obtained significant evidence of linkage on 2q with a peak log-of-odds ratio score (LOD) of 3.43 near marker D2S151 at 155 cM. To prioritize positional candidate genes at the 2q locus for detailed analysis, we applied an objective prioritization strategy that integrates quantitative bioinformatics, assessment of differential gene expression and association analysis of single-nucleotide polymorphisms (SNPs). Highest priority was assigned to the activin receptor gene ACVR2. This gene also showed >10-fold differential gene expression in human decidual tissue from normotensive and PE individuals. We genotyped five known SNPs in this gene in our pedigrees and performed tests for association and linkage disequilibrium. One SNP (rs1424954) showed strong preliminary evidence of association with PE (P = 0.007), whereas two others (rs1364658 and rs1895694) exhibited nominal evidence (P < 0.05). Haplotype analysis revealed no additional association information. There was evidence of weak linkage disequilibrium among these SNPs. The highest observed LD occurred between the two strongest associated SNPs, suggesting that the observed signals may be the signature of an observed functional variant.

    Title Diagnosis and Characterization of Fetal Sacrococcygeal Teratoma with Prenatal Mri.
    Date October 2006
    Journal Ajr. American Journal of Roentgenology
    Excerpt

    OBJECTIVE: The purpose of this study was to determine whether prenatal MRI provides additional information about fetal sacrococcygeal teratoma compared with prenatal sonography. MATERIALS AND METHODS: Twenty-two pregnant women with fetal sacrococcygeal teratoma underwent prenatal MRI (mean gestational age, 23 weeks). The size, location, mass characteristics, and compressive effects of the tumors were determined and correlated with sonography and postnatal findings. RESULTS: Based on the MRI findings, the following American Academy of Pediatrics, Surgical Section classifications were assigned: type I in six patients, type II in 12, and type III in four. No type IV tumors were found. The sacrococcygeal teratoma appeared entirely cystic in five fetuses, microcystic in one, mixed cystic and solid in 12, and solid in four. The diagnosis of sacrococcygeal teratoma was accurate in all cases assessed at our center using both MRI and sonography. Two additional patients initially referred with the diagnosis of sacrococcygeal teratoma had a different diagnosis at reevaluation at our institution (healthy, n = 1; myelomeningocele, n = 1). MRI was superior to sonography for detecting displacement of the colon (n = 11), urinary tract dilatation (n = 9), hip dislocation (n = 4), intraspinal extension (n = 2), and vaginal dilation (n = 1). In fetuses with sacrococcygeal teratoma types II and III, MRI better showed the cephalic extent of the tumor compared with sonography. MRI findings were confirmed at surgery or autopsy in all patients. Three fetuses with high output cardiac physiology underwent open fetal resection of the tumor at 21-, 24-, and 26-weeks' gestational age with two surviving. CONCLUSION: Our results show that ultrafast fetal MRI is a useful adjunct to the prenatal evaluation of fetal sacrococcygeal teratoma. Compared with sonography, MRI more accurately characterized the intrapelvic and abdominal extent of the tumors and provided more information on compression of adjacent organs. The additional anatomic resolution provided by MRI resulted in more accurate prenatal counseling and improved preoperative planning for surgical resection.

    Title Severe Pulmonary Hypoplasia Associated with Giant Cervical Teratomas.
    Date August 2006
    Journal Journal of Pediatric Surgery
    Excerpt

    BACKGROUND: The use of the ex utero intrapartum treatment (EXIT) procedure has salvaged many fetuses with giant neck masses. Despite an adequate airway, a subset of these patients die from an inability to achieve adequate gas exchange. METHODS: We reviewed our experience with the EXIT procedure from 1996 to 2004. The EXIT was used to deliver 23 fetuses with giant neck masses. RESULTS: Three fetuses with giant cervical teratomas died of severe pulmonary hypoplasia. On postmortem, these patients had severe airway distortion by the mass. The carina was retracted superiorly to the first or second rib resulting in compression of the lungs in the apices of the chest and pulmonary hypoplasia. Hypoplasia was reflected in the lung weights of 24 vs 38 g and 17 vs 34 g for age-matched normal lung. CONCLUSIONS: Unsuspected obstructive fetal neck masses can be fatal because of an inability to secure an airway. Prenatal ultrasonography can identify fetuses at risk, allowing the fetus to be salvaged using the EXIT procedure. Despite obtaining airway control, a subset of these patients will die because of pulmonary hypoplasia. When counseling patients with large cervical masses it is important to discuss potential pulmonary hypoplasia in these patients.

    Title Management of Fetal Mediastinal Teratoma.
    Date June 2006
    Journal Journal of Pediatric Surgery
    Excerpt

    BACKGROUND/PURPOSE: Mediastinal teratomas are rare congenital germ cell tumors that prenatally can compress mediastinal structures and cause hydrops. Two possible presentations of massive fetal mediastinal teratoma include hydrops leading to fetal demise, or fetal esophageal and airway compression causing late-gestation polyhydramnios and preterm labor. The authors present 2 cases of fetal mediastinal teratoma that illustrate successful strategies for either of these presentations. METHODS: A 37-year-old woman carrying a fetus with a mediastinal mass and secondary hydrops at 23 weeks of gestation underwent in utero resection of the mass. Delivery was by cesarean delivery at 25 weeks because of preterm labor. A 24-year-old mother carrying a fetus with a mediastinal mass and severe polyhydramnios at 36 weeks of gestation underwent an ex utero intrapartum therapy procedure for establishment of an airway and tumor resection on uteroplacental support. RESULTS: These strategies resulted in physiologic improvement in the first case and controlled resection and resuscitation in the second. The first patient had significant sequelae of prematurity including bronchopulmonary dysplasia but is currently well at 9 months of age. The second patient is well at 1 year of age. CONCLUSIONS: Massive fetal mediastinal teratoma can result in fetal or neonatal mortality by a variety of mechanisms. Optimal prenatal and perinatal management is required to salvage fetuses compromised by this lesion.

    Title The Ex Utero Intrapartum Therapy Procedure for High-risk Fetal Lung Lesions.
    Date May 2006
    Journal Journal of Pediatric Surgery
    Excerpt

    BACKGROUND: Indications for the ex utero intrapartum therapy (EXIT) procedure have expanded to include any fetal anomaly in which resuscitation of the neonate may be compromised. METHODS: We reviewed the medical records of 9 patients after resection of lung lesions during the EXIT procedure. RESULTS: The mean gestational age at EXIT procedure was 35.4 weeks. All lung masses maintained large sizes late into gestation with mean mass volume/head circumference ratio of 2.5 at presentation and 2.2 at EXIT. Seven of 9 fetuses demonstrated hydropic changes (n = 6) and/or polyhydramnios (n = 5), and underwent prenatal intervention including thoracentesis, thoracoamniotic shunt placement, amnioreduction, and/or betamethasone administration. Overall survival after EXIT for lung mass resection was 89%. The average time on placental bypass was 65 minutes. Postnatal complications included reoperation for air leak (n = 1), reoperation for bleeding (n = 1), and death from sepsis and prematurity (n = 1). Venoarterial extracorporeal membrane oxygenation was used in 4 neonates for persistent pulmonary hypertension. Maternal prenatal complications included polyhydramnios (n = 5), preterm labor (n = 4), and chorioamnionitis (n = 1). One mother required perioperative blood transfusion. CONCLUSION: The EXIT procedure allows for controlled resection of large fetal lung lesions at delivery, avoiding acute respiratory decompensation related to mediastinal shift, air trapping, and compression of normal lung.

    Title Maternal-fetal Surgery for Myelomeningocele: Neurodevelopmental Outcomes at 2 Years of Age.
    Date May 2006
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: This study was undertaken to examine short-term neurodevelopmental outcomes in children with myelomeningocele (MMC) who underwent in utero neurosurgical closure. STUDY DESIGN: Between 1998 and 2002, 51 fetuses underwent in utero MMC closure at our Center. Thirty (63%) of these children have returned for neurodevelopmental testing at 2 years of age using the Bayley Scales of Infant Development and Preschool Language Scales. RESULTS: Overall shunt rate was 43% in this group. Neurodevelopmental testing found 67% with cognitive language and personal-social skills in the normal range, 20% with mild delays, and 13% with significant delays. Children with shunted hydrocephalus scored lower than those with unshunted ventriculomegaly. CONCLUSION: Children who have undergone fetal MMC closure have characteristic neurodevelopmental deficits that do not appear worsened by fetal surgery, and developmental outcomes may be improved by decreasing the need for ventriculoperitoneal shunting.

    Title Fetal Posterior Fossa Volume: Assessment with Mr Imaging.
    Date April 2006
    Journal Radiology
    Excerpt

    PURPOSE: To retrospectively determine the relationship between posterior fossa volume (PFV) and estimated gestational age (EGA) and/or femur length (FL) during pregnancy for the purpose of developing a normal growth curve. MATERIALS AND METHODS: Advance institutional review board approval was obtained for this HIPAA-compliant study, and the need for parent informed consent was waived. A cross-sectional retrospective study was performed to measure PFV on in vivo magnetic resonance (MR) images obtained in 76 fetuses of 18-36 weeks gestation who had a morphologically normal CNS. Because this was a retrospective series, MR imaging techniques varied slightly, but all fetuses underwent imaging at contiguous 3-5-mm intervals in at least two orthogonal planes, with repetition time msec/echo time msec, 5-12/62-95; number of signals acquired, one; flip angle, 150 degrees -180 degrees; and matrix, 128-192 x 256. Posterior fossa areas were manually traced on half-Fourier rapid acquisition with relaxation enhancement in utero fetal MR images by one observer. PFVs were then calculated by manually summing areas from the contiguous sections and multiplying the total area by the section thickness. An average PFV (APFV) across orthogonal planes was calculated for each fetus, and the relationship between APFV and EGA was mathematically modeled. Coronal, transverse, and sagittal views were compared with correlations and Bland-Altman plots. Two additional observers repeated the measurements for a small subset of fetuses (n = 5). Paired t test analyses were also performed to determine significant differences between sagittal, transverse, and coronal measurements, as well as to determine preliminary intraobserver and interobserver variability of measurements in a subset of cases. RESULTS: The relationship between APFV (in cubic centimeters) and EGA (in weeks) was well described by a single exponential function [APFV = 0.689 exp(EGA/9.10)]. APFV doubling time was 6.31 weeks. Root-mean-square variation of values around the model line was 1.63 cm(3). There was no statistically significant intra- or interobserver variation (P > .16 for all fetuses) at preliminary analysis. No correlation between APFV and FL could be found. CONCLUSION: The normal fetal PFV growth curve generated in this study may have potential as a model for clinical application.

    Title Cystic Adenomatoid Malformation of the Lung: Review of Genetics, Prenatal Diagnosis, and in Utero Treatment.
    Date April 2006
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Prenatal identification of lung abnormalities has increased with prenatal surveillance. Treatment usually requires serial ultrasound observation but in rare situations in utero therapy may be required for fetal survival. We review the genetics, prenatal evaluation, and treatment of lung abnormalities with congenital cystic adenomatoid malformation (CCAM). Other lung lesions, bronchopulmonary sequestration (BPS), hybrid lesions involving both malformations, congenital lobar emphysema (CLE), are briefly included as differential diagnosis options. Outcome of fetuses identified to have CCAM lung abnormalities resulting in fetal hydrops and having in utero therapy (thoracoamniotic shunting, fetal thoracotomy, EXIT delivery) are discussed. In the appropriate situation, this maternal fetal surgery approach for CCAM is life-saving for the affected fetus with acceptable maternal morbidity risks in the present and future pregnancies.

    Title A Population Genomics Overview of the Neuronal Nitric Oxide Synthase (nnos) Gene and Its Relationship to Migraine Susceptibility.
    Date March 2006
    Journal Cellular and Molecular Biology (noisy-le-grand, France)
    Excerpt

    The ubiquitous chemical messenger molecule nitric oxide (NO) has been implicated in a diverse range of biological activities including neurotransmission, smooth muscle motility and mediation of nociception. Endogenous synthesis of NO by the neuronal isoform of the nitric oxide synthase gene family has an essential role within the central and peripheral nervous systems in addition to the autonomic innervation of cerebral blood vessels. To investigate the potential role of NO and more specifically the neuronal nitric oxide synthase (nNOS) gene in migraine susceptibility, we investigated two microsatellite repeat variants residing within the 5' and 3' regions of the nNOS gene. Population genomic evaluation of the two nNOS repeat variants indicated significant linkage disequilibrium between the two loci. Z-DNA conformational sequence structures within the 5' region of the nNOS gene have the potential to enhance or repress gene promoter activity. We suggest that genetic analysis of this 5' repeat variant is the more functional variant expressing gene wide information that could affect endogenous NO synthesis and potentially result in diseased states. However, no association with migraine (with or without aura) was seen in our extensive case-control cohort (n = 579 affected with matched controls), when both the 5' and 3' genetic variants were investigated.

    Title Leadership Competencies: an Introduction.
    Date March 2006
    Journal Journal of Healthcare Management / American College of Healthcare Executives
    Title A Genetic Analysis of Serotonergic Biosynthetic and Metabolic Enzymes in Migraine Using a Dna Pooling Approach.
    Date February 2006
    Journal Journal of Human Genetics
    Excerpt

    Migraine is a common debilitating primary headache disorder with significant mental, physical and social health implications. The brain neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) is involved in nociceptive pathways and has been implicated in the pathophysiology of migraine. With few genetic studies investigating biosynthetic and metabolic enzymes governing the rate of 5-HT activity and their relationship to migraine, it was the objective of this study to assess genetic variants within the human tryptophan hydroxylase (TPH), amino acid decarboxylase (AADC) and monoamine oxidase A (MAOA) genes in migraine susceptibility. This objective was undertaken using a high-throughput DNA pooling experimental design, which proved to be a very accurate, sensitive and specific method of estimating allele frequencies for single nucleotide polymorphism, insertion deletion and variable number tandem repeat loci. Application of DNA pooling to a wide array of genetic loci provides greater scope in the assessment of population-based genetic association study designs. Despite the application of this high-throughput genotyping method, negative results from the two-stage DNA pooling design used to screen loci within the TPH, AADC and MAOA genes did not support their role in migraine susceptibility.

    Title Off-axis Effects on the Multipulse Structure of Sperm Whale Usual Clicks with Implications for Sound Production.
    Date February 2006
    Journal The Journal of the Acoustical Society of America
    Excerpt

    Sperm whales (Physeter macrocephalus) produce multipulsed clicks with their hypertrophied nasal complex. The currently accepted view of the sound generation process is based on the click structure measured directly in front of, or behind, the whale where regular interpulse intervals (IPIs) are found between successive pulses in the click. Most sperm whales, however, are recorded with the whale in an unknown orientation with respect to the hydrophone where the multipulse structure and the IPI do not conform to a regular pulse pattern. By combining far-field recordings of usual clicks with acoustic and orientation information measured by a tag on the clicking whale, we analyzed clicks from known aspects to the whale. We show that a geometric model based on the bent horn theory for sound production can explain the varying off-axis multipulse structure. Some of the sound energy that is reflected off the frontal sac radiates directly into the water creating an intermediate pulse p1/2 seen in off-axis recordings. The powerful p1 sonar pulse exits the front of the junk as predicted by the bent-horn model, showing that the junk of the sperm whale nasal complex is both anatomically and functionally homologous to the melon of smaller toothed whales.

    Title Historical Perspectives of Autonomy Within the Medical Profession: Considerations for 21st Century Physical Therapy Practice.
    Date January 2006
    Journal The Journal of Orthopaedic and Sports Physical Therapy
    Excerpt

    As a part of the American Physical Therapy Association's (APTA) vision statement, by the year 2020, physical therapists "will hold all privileges of autonomous practice." This vision statement and the ideals held within it are elemental to the direction of our continued growth as a profession. Many members and nonmembers, however, appear confused and perhaps even intimidated by the concept of autonomous practice. This paper will review and discuss the processes used by other health care professions to gain autonomy within the US health care system. In particular, the processes used by physicians, which were extremely effective and have been used as a template by many other health professions, including physical therapy. Further discussion will focus on the physical therapy profession, emphasizing the parallels with medicine and considering many issues relevant to the goal of autonomous practice. By understanding the past and considering the present, readers will develop an appreciation of (1) the foundation for autonomous practice in health care, (2) the vision of the APTA and why the profession is well positioned to achieve this vision, and (3) the factors we need to consider to hold (and maintain) all privileges of autonomous practice.

    Title Echolocation Clicks of Free-ranging Cuvier's Beaked Whales (ziphius Cavirostris).
    Date December 2005
    Journal The Journal of the Acoustical Society of America
    Excerpt

    Strandings of beaked whales of the genera Ziphius and Mesoplodon have been reported to occur in conjunction with naval sonar use. Detection of the sounds from these elusive whales could reduce the risk of exposure, but descriptions of their vocalizations are at best incomplete. This paper reports quantitative characteristics of clicks from deep-diving Cuvier's beaked whales (Ziphius cavirostris) using a unique data set. Two whales in the Ligurian Sea were simultaneously tagged with sound and orientation recording tags, and the dive tracks were reconstructed allowing for derivation of the range and relative aspect between the clicking whales. At depth, the whales produced trains of regular echolocation clicks with mean interclick intervals of 0.43 s (+/- 0.09) and 0.40 s (+/- 0.07). The clicks are frequency modulated pulses with durations of approximately 200 micros and center frequencies around 42 kHz, -10 dB bandwidths of 22 kHz, and Q(3 dB) of 4. The sound beam is narrow with an estimated directionality index of more than 25 dB, source levels up to 214 dB(pp) re: 1 microPa at 1 m, and energy flux density of 164 dB re: 1 microPa2 s. As the spectral and temporal properties are different from those of nonziphiid odontocetes the potential for passive detection is enhanced.

    Title Understanding Technology Adoption in Clinical Care: Clinician Adoption Behavior of a Point-of-care Reminder System.
    Date November 2005
    Journal International Journal of Medical Informatics
    Excerpt

    BACKGROUND: Evaluation studies of clinical decision support systems (CDSS) have tended to focus on assessments of system quality and clinical performance in a laboratory setting. Relatively few studies have used field trials to determine if CDSS are likely to be used in routine clinical settings and whether reminders generated are likely to be acted upon by end-users. Moreover, such studies when performed tend not to identify distinct user groups, nor to classify user feedback. AIM: To assess medical residents' acceptance and adoption of a clinical reminder system for chronic disease and preventive care management and to use expressed preferences for system attributes and functionality as a basis for system re-engineering. DESIGN OF STUDY: Longitudinal, correlational study using a novel developmental trajectory analysis (DTA) statistical method, followed by a qualitative analysis based on user satisfaction surveys and field interviews. SETTING: An ambulatory primary care clinic of an urban teaching hospital offering comprehensive healthcare services. 41 medical residents used a CDSS over 10 months in their daily practice. Use of this system was strongly recommended but not mandatory. METHODS: A group-based, semi-parametric statistical modeling method to identify distinct groups, with distinct usage trajectories, followed by qualitative instruments of usability and satisfaction surveys and structured interviews to validate insights derived from usage trajectories. RESULTS: Quantitative analysis delineates three types of user adoption behavior: "light", "moderate" and "heavy" usage. Qualitative analysis reveals that clinicians of distinct types tend to exhibit views of the system consistent with their demonstrated adoption behavior. Drawbacks in the design of the CDSS identified by users of all types (in different ways) motivate a redesign based on current physician workflows. CONCLUSION: We conclude that this mixed methodology has considerable promise to provide new insights into system usability and adoption issues that may benefit clinical decision support systems as well as information systems more generally.

    Title Long-term Outcomes in Children Treated by Prenatal Vesicoamniotic Shunting for Lower Urinary Tract Obstruction.
    Date November 2005
    Journal Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Limited information is available about long-term outcomes in children treated prenatally for lower urinary tract obstruction. Our aim was to evaluate outcomes in children treated in utero with vesicoamniotic shunts. METHODS: Clinical outcomes in 20 pregnancies with a singleton male fetus, oligo/anhydramnios, and lower urinary tract obstruction were studied using chart review and phone and written clinical questionnaire for parents, pediatricians, and urologists. RESULTS: Overall 1-year survival was 91%. Two neonatal deaths occurred from pulmonary hypoplasia. Mean gestational age at delivery was 34.6 weeks, mean days from shunting to delivery were 84.4, and mean birth weight was 2,574 g. Prenatal urinary prognosis was good in 13, borderline in 2, and poor in 3 of the survivors. Mean age at follow-up was 5.83 years. Posterior urethral valves were confirmed in 7 males, urethral atresia in 4, and prune belly syndrome in 7. Eight children had acceptable renal function, 4 had mild insufficiency, and 6 required dialysis and eventual renal transplant. Eleven children had normal bladder function with spontaneous voiding, 6 required catheterization, and 1 child still had a vesicostomy. Height and weight were below the 25th percentile in 9 children. Persistent respiratory problems were present in 8, musculoskeletal problems in 9, and frequent urinary tract infections were reported in 9. Health-related quality of life results in our group with lower urinary tract obstruction were similar to those in a healthy child population. CONCLUSION: Male children who underwent prenatal bladder shunting were neurodevelopmentally normal. Although one third of the surviving babies required dialysis and transplantation, the majority have acceptable renal and bladder function and report satisfactory quality of life. LEVEL OF EVIDENCE: III.

    Title Metabotropic Glutamate 2 Receptor Potentiators: Receptor Modulation, Frequency-dependent Synaptic Activity, and Efficacy in Preclinical Anxiety and Psychosis Model(s).
    Date October 2005
    Journal Psychopharmacology
    Excerpt

    RATIONALE: To increase subtype selectivity and provide a novel means to alter receptor function, we discovered and characterization potentiators for the metabotropic glutamate 2 receptor (mGlu2). METHODS AND RESULTS: A class of 3-pyridylmethylsulfonamides (e.g., 3-MPPTS; 2,2,2-trifluoro-N-[3-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide) were found to be potent, subtype-selective potentiators of human and rat mGlu2. The sulfonamides increased agonist potency in functional assays but did not displace orthosteric radiolabeled antagonist or agonist binding to cloned mGlu2 receptors. Rather, the modulators increased the affinity of most of the orthosteric agonists including glutamate, DCG-IV (2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl)glycine), and LY354740 (1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate). In striatal brain slices, LY354740 inhibited evoked excitatory postsynaptic potentials (EPSPs) equally well following either a low- (0.06 Hz) or high (4 Hz)-frequency stimulation of corticostriatal afferents. In contrast, the mGlu2 potentiator cyPPTS (2,2,2-trifluoro-N-[3-(cyclopentyloxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide) inhibited striatal EPSPs only at higher frequencies of stimulation (2 and 4 Hz). Several sulfonamides including 4-MPPTS, 4-APPES (N-[4-(4-carboxamidophenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride monohydrate) and/or CBiPES N-[4'-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride) were tested in mGlu2/3 agonist-sensitive rodent model(s) of anxiety and psychosis. As seen with LY354740, both 4-MPPTS and 4-APPES were efficacious in a rat fear-potentiated startle paradigm. Likewise in mice, CBiPES attenuated a stress-induced hyperthermia and PCP-induced hyperlocomotor activity. Furthermore, CBiPES mediated alteration in PCP-induced hyperlocomotor activity was sensitive to mGlu2/3 antagonist pretreatment. CONCLUSIONS: Taken together, the data indicate mGlu2 receptor potentiators have a unique use-dependent effect on presynaptic glutamate release, and show efficacy in several mGlu2/3-sensitive animal models of psychiatric disorders.

    Title Fetal Surgical Intervention.
    Date October 2005
    Journal Surgical Technology International
    Title Variation in the Vitamin D Receptor Gene is Associated with Multiple Sclerosis in an Australian Population.
    Date September 2005
    Journal Journal of Neurogenetics
    Excerpt

    Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) resulting in accumulating neurological disability. The disorder is more prevalent at higher latitudes. To investigate VDR gene variation using three intragenic restriction fragment length polymorphisms (Apa I, Taq I and Fok I) in an Australian MS case-control population. One hundred and four Australian MS patients were studied with patients classified clinically as Relapsing Remitting MS (RR-MS), Secondary Progressive MS (SP-MS) or Primary Progressive MS (PP-MS). Also, 104 age-, sex-, and ethnicity-matched controls were investigated as a comparative group. Our results show a significant difference of genotype distribution frequency between the case and control groups for the functional exon 9 VDR marker Taq I (p(Gen) = 0.016) and interestingly, a stronger difference for the allelic frequency (p(All) = 0.0072). The Apa I alleles were also found to be associated with MS (p(All) = 0.04) but genotype frequencies were not significantly different from controls (p(Gen) = 0.1). The Taq and Apa variants are in very strong and significant linkage disequilibrium (D' = 0.96, P < 0.0001). The genotypic associations are strongest for the progressive forms of MS (SP-MS and PP-MS). Our results support a role for the VDR gene increasing the risk of developing multiple sclerosis, particularly the progressive clinical subtypes of MS.

    Title Impact of Continuous Intraoperative Monitoring on Outcomes in Open Fetal Surgery.
    Date September 2005
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVES: There are shifts in fetal hemodynamics during open fetal surgery that were not appreciated until the use of intraoperative fetal echocardiography. We have developed an intraoperative monitoring strategy to continuously assess fetal hemodynamics. We hypothesized that this approach would enhance intraoperative management and survival. METHODS: Medical records of open fetal surgery patients were reviewed since the implementation of this approach. Intraoperative fetal monitoring was accomplished by continuous echocardiography, pulse oximetry, establishment of intravenous access, and arterial blood gas and hemoglobin measurement. Overall survival was compared to fetal surgeries performed prior implementation of this monitoring strategy. RESULTS: Resections of a congenital cystic adenomatoid malformation or a sacrococcygeal teratoma in nine hydropic fetuses were performed while using this monitoring strategy. Intraoperative echocardiography resulted in a change of management in 7 of 9 fetuses. The main observations on fetal echocardiography resulting in intraoperative intervention were decreased ventricular filling, bradycardia, and decreased ventricular contractility. Therapy included administration of volume expanders and/or inotropic agents. Overall fetal survival was 78% compared to a survival of 42% prior to the implementation of this approach. CONCLUSION: Continuous intraoperative fetal monitoring provides real time assessment of fetal hemodynamics which results in changes in intraoperative management. The overall outcomes in these critically ill fetuses have been improved.

    Title Physical Therapist Management of an Adult with Osteochondritis Dissecans of the Knee.
    Date August 2005
    Journal Physical Therapy
    Excerpt

    BACKGROUND AND PURPOSE: Osteochondritis dissecans (OCD) primarily occurs between 10 and 20 years of age. Adult patients (>20 years) tend to respond poorly to nonsurgical management. This case report describes the physical therapist management of an adult with OCD at the tibiofemoral joint. CASE DESCRIPTION: A 24-year-old woman had insidious onset of right knee pain. Magnetic resonance imaging confirmed the diagnosis of OCD. Interventions included iontophoresis, strengthening exercises, and instruction in strategies to minimize loading across the knee. OUTCOME: The patient received 5 intervention sessions. At discharge and 9-month follow-up, she reported 95% function (Single Assessment Numeric Evaluation) and no pain while performing full work duties. DISCUSSION: This case illustrates the process, including the use of evidence, of making clinical decisions about the physical therapist management of an adult with OCD.

    Title An Adoption Study of a Clinical Reminder System in Ambulatory Care Using a Developmental Trajectory Approach.
    Date June 2005
    Journal Studies in Health Technology and Informatics
    Excerpt

    In this study, we assess 41 medical residents' acceptance and adoption of a clinical reminder system for chronic disease and preventive care management in the ambulatory care environment using a novel developmental trajectory approach. This group-based, semi-parametric statistical modeling method identifies distinct groups, following distinct usage trajectories, among those who recorded use of the reminder system within an evaluation period of 10 months. We trace system use within these groups over time using computer-generated logs and user satisfaction surveys. Our preliminary analysis of this small sample of users delineates three categories of users. Feedback from these categories of users is being used to re-engineer the application and adapt it better to their workflow and functionality requirements. Despite the small sample size in this particular study, we conclude that this methodology has considerable promise to provide new insights into system usability and adoption issues that may benefit clinical decision support systems as well as information systems more generally.

    Title Acute Cardiovascular Effects of Fetal Surgery in the Human.
    Date June 2005
    Journal Circulation
    Excerpt

    BACKGROUND: Prenatal surgery for congenital anomalies can prevent fetal demise or alter the course of organ development, resulting in a more favorable condition at birth. The indications for fetal surgery continue to expand, yet little is known about the acute sequelae of fetal surgery on the human cardiovascular system. METHODS AND RESULTS: Echocardiography was used to evaluate the heart before, during, and early after fetal surgery for congenital anomalies, including repair of myelomeningocele (MMC, n=51), resection of intrathoracic masses (ITM, n=15), tracheal occlusion for congenital diaphragmatic hernia (CDH, n=13), and resection of sacrococcygeal teratoma (SCT, n=4). Fetuses with MMC all had normal cardiovascular systems entering into fetal surgery, whereas those with ITM, CDH, and SCT all exhibited secondary cardiovascular sequelae of the anomaly present. At fetal surgery, heart rate increased acutely, and combined cardiac output diminished at the time of fetal incision for all groups including those with MMC, which suggests diminished stroke volume. Ventricular dysfunction and valvular dysfunction were identified in all groups, as was acute constriction of the ductus arteriosus. Fetuses with ITM and SCT had the most significant changes at surgery. CONCLUSIONS: Acute cardiovascular changes take place during fetal surgery that are likely a consequence of the physiology of the anomaly and the general effects of surgical stress, tocolytic agents, and anesthesia. Echocardiographic monitoring during fetal surgery is an important adjunct in the management of these patients.

    Title Three-dimensional Beam Pattern of Regular Sperm Whale Clicks Confirms Bent-horn Hypothesis.
    Date May 2005
    Journal The Journal of the Acoustical Society of America
    Excerpt

    The three-dimensional beam pattern of a sperm whale (Physeter macrocephalus) tagged in the Ligurian Sea was derived using data on regular clicks from the tag and from hydrophones towed behind a ship circling the tagged whale. The tag defined the orientation of the whale, while sightings and beamformer data were used to locate the whale with respect to the ship. The existence of a narrow, forward-directed P1 beam with source levels exceeding 210 dBpeak re: 1 microPa at 1 m is confirmed. A modeled forward-beam pattern, that matches clicks >20 degrees off-axis, predicts a directivity index of 26.7 dB and source levels of up to 229 dBpeak re: 1 microPa at 1 m. A broader backward-directed beam is produced by the P0 pulse with source levels near 200 dBpeak re: 1 microPa at 1 m and a directivity index of 7.4 dB. A low-frequency component with source levels near 190 dBpeak re: 1 microPa at 1 m is generated at the onset of the P0 pulse by air resonance. The results support the bent-horn model of sound production in sperm whales. While the sperm whale nose appears primarily adapted to produce an intense forward-directed sonar signal, less-directional click components convey information to conspecifics, and give rise to echoes from the seafloor and the surface, which may be useful for orientation during dives.

    Title Implications of Coping Repertoire As Predictors of Men's Stress, Anxiety and Depression Following Pregnancy, Childbirth and Miscarriage: a Longitudinal Study.
    Date May 2005
    Journal Journal of Psychosomatic Obstetrics and Gynaecology
    Excerpt

    The long-term implication of how men cope during a partner's pregnancy, at childbirth or following miscarriage has not received attention. This study aims to examine if men's coping response during pregnancy, at childbirth, or miscarriage predict psychological outcomes at the time of childbirth/miscarriage or 1 year later, and to establish whether there are any changes in men's coping repertoire. Utilizing a longitudinal design, 384 volunteer expectant fathers, participated by completing measures of stress, anxiety, depression and coping during their partner's pregnancy, following childbirth or miscarriage, and 1 year later. Findings indicated, at the time of childbirth/miscarriage, increases on all psychological outcomes compared to during the pregnancy, which then decreased at 1-year. During pregnancy, men relied more on approach-orientated coping, changing at pregnancy outcome to avoidant-orientated strategies. Regression revealed the best predictor of psychological outcome, in the long-term, was coping response at pregnancy outcome. However each psychological outcome had its own predictive path, varying depending on pregnancy outcome; supporting the concept that coping responses are situationally specific, changing depending on the event examined. How men cope with each aspect of their reproductive experiences may have implications for the provision of support they offer their partner, and the support they themselves need.

    Title Fetal Head Biometry Following In-utero Repair of Myelomeningocele.
    Date April 2005
    Journal Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: To evaluate the impact of prenatal myelomeningocele repair on fetal head biometry. METHODS: Fifty fetuses underwent open fetal myelomeningocele repair at our institution between January 1998 and July 2002. All had serial head circumference (HC) and lateral ventricular diameter (VD) measurements taken preoperatively and weekly for 8 weeks after repair. Cortical index (CI) was defined as HC/VD. Measurements were compared with gestational age-matched values from nomograms. One-sample t-test, ANOVA and repeated measures analysis were used to assess HC, VD and CI after fetal repair. RESULTS: Preoperatively, the HC in fetuses with myelomeningocele was smaller than control values (186.4 vs. 198.8 mm, P = 0.0004). Eight weeks' postoperatively this difference had resolved (293 vs. 301.6 mm, P = 0.76). The mean increase in CI after repair was 20% (P = 0.02) compared with the predicted 51% in normal cases. The average increase in VD was 3.9 mm (38.8%, P < 0.001). CONCLUSIONS: Mid-gestational repair of myelomeningocele alters fetal head growth. Increased CI suggests HC changes are not due to ventriculomegaly alone.

    Title Prenatal Diagnosis and Management of Mainstem Bronchial Atresia.
    Date April 2005
    Journal Fetal Diagnosis and Therapy
    Excerpt

    The prenatal diagnosis, natural history and management of mainstem bronchial atresia have not been described previously. We report two cases of prenatally diagnosed proximal bronchial atresia. The first patient presented at 18 weeks with sonographic and MRI findings consistent with bronchial atresia with fetal hydrops. The mother developed the mirror syndrome and labor was induced. A non-viable fetus was delivered at 25 weeks. The second patient presented at 16 weeks gestation with evidence of an intrathoracic mass that was subsequently prenatally diagnosed as a right mainstem bronchial atresia. The right lung increased rapidly in size and was associated with the onset of fetal hydrops. At 24 weeks, fetal pneumonectomy was performed but the fetus expired intraoperatively due to cardiovascular collapse. Post-mortem findings in both cases confirmed the presence of an atretic mainstem bronchus with massive enlargement of the lung. Bronchial atresia involving the mainstem bronchus is associated with a poor prognosis.

    Title Ascent Exhalations of Antarctic Fur Seals: a Behavioural Adaptation for Breath-hold Diving?
    Date April 2005
    Journal Proceedings. Biological Sciences / The Royal Society
    Excerpt

    Novel observations collected from video, acoustic and conductivity sensors showed that Antarctic fur seals consistently exhale during the last 50-85% of ascent from all dives (10-160 m, n > 8000 dives from 50 seals). The depth of initial bubble emission was best predicted by maximum dive depth, suggesting an underlying physical mechanism. Bubble sound intensity recorded from one seal followed predictions of a simple model based on venting expanding lung air with decreasing pressure. Comparison of air release between dives, together with lack of variation in intensity of thrusting movement during initial descent regardless of ultimate dive depth, suggested that inhaled diving lung volume was constant for all dives. The thrusting intensity in the final phase of ascent was greater for dives in which ascent exhalation began at a greater depth, suggesting an energetic cost to this behaviour, probably as a result of loss of buoyancy from reduced lung volume. These results suggest that fur seals descend with full lung air stores, and thus face the physiological consequences of pressure at depth. We suggest that these regular and predictable ascent exhalations could function to reduce the potential for a precipitous drop in blood oxygen that would result in shallow-water blackout.

    Title Allosteric Modulators of Metabotropic Glutamate Receptors: Lessons Learnt from Mglu1, Mglu2 and Mglu5 Potentiators and Antagonists.
    Date April 2005
    Journal Biochemical Society Transactions
    Excerpt

    Although relatively few G-protein-coupled receptors are Class C, in recent years, this small family of receptors has become a focal point for the discovery of new and exciting allosteric modulators. The mGlu (metabotropic glutamate) receptors are illustrative in the discovery of both positive and/or negative allosteric modulators with unique pharmacological properties. For instance, allosteric modulators of the mGlu2 receptor act as potentiators of glutamate responses in clonal expression systems and in native tissue assays. These potentiators act to increase the affinity of orthosteric agonists for the mGlu2 receptor and shift potency curves for the agonist to the left. In electrophysiological experiments, the potentiators show a unique activation-state-dependent presynaptic inhibition of glutamate release and significantly enhance the receptor-mediated increase in G-protein binding, as seen with autoradiography. Similarly, potentiators of mGlu5 have been described, as well as allosteric antagonists or inverse agonists of mGlu1 and mGlu5. Binding and activity of the modulators have recently indicated that positive and negative allosteric sites can be, but are not necessarily, overlapping. Compared with orthosteric ligands, these modulators display a unique degree of subtype selectivity within the highly conserved mGlu family of receptors and can have very distinct pharmacological properties, such as neuronal frequency-dependent activity. This short review describes some of the unique features of these mGlu1, mGlu2 and mGlu5 allosteric modulators.

    Title Metabotropic Glutamate Receptors As Novel Targets for Anxiety and Stress Disorders.
    Date March 2005
    Journal Nature Reviews. Drug Discovery
    Excerpt

    Anxiety and stress disorders are the most commonly occurring of all mental illnesses, and current treatments are less than satisfactory. So, the discovery of novel approaches to treat anxiety disorders remains an important area of neuroscience research. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and G-protein-coupled metabotropic glutamate (mGlu) receptors function to regulate excitability via pre- and postsynaptic mechanisms. Various mGlu receptor subtypes, including group I (mGlu(1) and mGlu(5)), group II (mGlu(2) and mGlu(3)), and group III (mGlu(4), mGlu(7) and mGlu(8)) receptors, specifically modulate excitability within crucial brain structures involved in anxiety states. In addition, agonists for group II (mGlu(2/3)) receptors and antagonists for group I (in particular mGlu(5)) receptors have shown activity in animal and/or human conditions of fear, anxiety or stress. These studies indicate that metabotropic glutamate receptors are interesting new targets to treat anxiety disorders in humans.

    Title A Pilot Program Takes Flight: the North Carolina Practitioner Remediation and Enhancement Partnership Experience.
    Date February 2005
    Journal Jona's Healthcare Law, Ethics and Regulation
    Title Congenital Abdominal Wall Defects: an Update.
    Date January 2005
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To review published peer-reviewed literature regarding abdominal wall defects including gastroschisis and omphalocele. METHODS: Review of published peer-reviewed literature using Med Line 1985-2003 and textbooks. RESULTS: Gastroschisis and omphalocele literature is reviewed using pathology, incidence and epidemiology, prenatal evaluation, pregnancy and delivery management, postnatal outcome and fetal therapy. CONCLUSION: Gastroschisis and omphalocele are common abdominal wall defects and have significant morbidity and mortality.

    Title Thoracoamniotic Shunts: Fetal Treatment of Pleural Effusions and Congenital Cystic Adenomatoid Malformations.
    Date January 2005
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To determine whether fetuses that underwent thoracoamniotic shunt placement for treatment of pleural effusion (PE) or macrocystic congenital cystic adenomatoid malformation (CCAM) have an improved outcome as compared with an untreated population. METHODS: A retrospective review from a single tertiary center was performed using thoracoamniotic shunt placement to treat PE or macrocystic CCAM between 1998 and 2001. Thoracoamniotic shunts were used on 26 occasions in 19 pregnancies. RESULTS: The average gestational age at the diagnosis of PE and CCAM was 22 + 4 and 20 + 0 weeks, respectively. Shunts were offered in pregnancies complicated by hydrops or at significant risk for pulmonary hypoplasia. Shunts were placed at 26 + 2 weeks (average) and 23 + 1 weeks (average) in the PE and CCAM groups, respectively. In CCAM patients, the mean pre- and postshunting mass volumes were 50.5 and 25.7 cm(3), representing a 51% reduction in mass volume following shunt placement. In the PE group, the average delivery age was 33 + 5 weeks, with an average shunt placement to delivery time of 7 + 3 weeks. In the CCAM group, the average delivery was 33 + 3 weeks, with an average shunt placement to delivery time of 10 + 2 weeks. The postnatal survival rates were 67% (6/9) and 70% (7/10) in the PE and CCAM groups, respectively. CONCLUSIONS: (1) Thoracoamniotic shunts should be considered as a treatment option for selected PE or macrocystic CCAM fetuses with hydrops or a significant risk for pulmonary hypoplasia; (2) the neonatal survival with shunting was similar for PE and CCAM groups and was improved as compared with literature reports, and (3) fetuses with CCAM presented earlier with hydrops than those with PE. Successful shunting resulted in a prolongation of pregnancy into the 3rd trimester in both groups.

    Title Sperm Whale Behaviour Indicates the Use of Echolocation Click Buzzes "creaks" in Prey Capture.
    Date January 2005
    Journal Proceedings. Biological Sciences / The Royal Society
    Excerpt

    During foraging dives, sperm whales (Physeter macrocephalus) produce long series of regular clicks at 0.5-2 s intervals interspersed with rapid-click buzzes called "creaks". Sound, depth and orientation recording Dtags were attached to 23 whales in the Ligurian Sea and Gulf of Mexico to test whether the behaviour of diving sperm whales supports the hypothesis that creaks are produced during prey capture. Sperm whales spent most of their bottom time within one or two depth bands, apparently feeding in vertically stratified prey layers. Creak rates were highest during the bottom phase: 99.8% of creaks were produced in the deepest 50% of dives, 57% in the deepest 15% of dives. Whales swam actively during the bottom phase, producing a mean of 12.5 depth inflections per dive. A mean of 32% of creaks produced during the bottom phase occurred within 10 s of an inflection (13x more than chance). Sperm whales actively altered their body orientation throughout the bottom phase with significantly increased rates of change during creaks, reflecting increased manoeuvring. Sperm whales increased their bottom foraging time when creak rates were higher. These results all strongly support the hypothesis that creaks are an echolocation signal adapted for foraging, analogous to terminal buzzes in taxonomically diverse echolocating species.

    Title Sar Study of a Subtype Selective Allosteric Potentiator of Metabotropic Glutamate 2 Receptor, N-(4-phenoxyphenyl)-n-(3-pyridinylmethyl)ethanesulfonamide.
    Date January 2005
    Journal Bioorganic & Medicinal Chemistry Letters
    Excerpt

    The major excitatory neurotransmitter in the Central Nervous System is L-glutamic acid. As a result much attention has been given to the discovery of selective modulators of both the ionotropic glutamate receptors (iGluRs) and the metabotropic glutamate receptors (mGluRs). In this study we describe a novel class of subtype selective allosteric potentiators of the mGlu2 receptor. An active compound N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide, LY181837, was identified in the course of compound screening. The synthesis of two series of analogs examined the structural requirements of the diaryl region of this compound. This SAR study also resulted in compounds with an increase in potency of over 100-fold where the most potent compound reported has EC(50)=14 nM.

    Title Reproductive Outcomes After Pregnancy Complicated by Maternal-fetal Surgery.
    Date December 2004
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: The reproductive outcomes for women after the pregnancy complicated by maternal-fetal surgery were evaluated to obtain evidence-based information for prenatal risk counseling. STUDY DESIGN: The retrospective review identified 83 women with maternal-fetal surgery from a single institution (1996-2002). These women were sent a consent form and a questionnaire to document postoperative problems, fertility, obstetric outcomes, and psychosocial concerns in pregnancy after the index fetal therapy. Institutional Review Board approval was obtained from Committee for Protection of Human Subjects. RESULTS: The total return rate was 55 (66%). The pregnancy rate was 62% (18% spontaneous abortion, 24% preterm delivery, and 58% term delivery). Complications were reported in 12 of 34 pregnancies (35%), including uterine dehiscence/rupture (12%/6%), cesarean hysterectomy (3%), and antepartum hemorrhage requiring transfusion (9%). CONCLUSION: The reproductive outcome of uterine dehiscence, rupture, and hysterectomy was 12%, 6%, and 3%, respectively, after a pregnancy complicated by maternal-fetal surgery. The uterine rupture rate is similar to the rupture rate after "classical" cesarean section (4%-9%).

    Title Prenatally Diagnosed Giant Omphaloceles: Short- and Long-term Outcomes.
    Date October 2004
    Journal Prenatal Diagnosis
    Excerpt

    OBJECTIVES: To review prenatal findings, short- and long-term outcomes of giant omphaloceles (GO) managed at a single institution (1996-2001). METHODS: Prenatal findings and early postnatal outcomes were retrospectively reviewed. Clinical short- and long-term outcomes were analyzed in eight and five children respectively. Parents and physicians of the children were surveyed by written questionnaires about the children's subsequent health issues. (IRB 2002-2-2683). RESULTS: Seventeen pregnancies with GO were identified: Eight fetuses were live born, four ended in (terminations), two died in utero and three were lost to follow-up. Live-born fetuses had prenatal ascites, extreme levocardia and were delivered by cesarean section at a mean of 37 weeks' gestation with a mean birth weight of 2903 g. All neonates required intubation. Two infants (2/8) died within one year. Four of the six survivors had respiratory insufficiency with a mean ventilation time of 76 days. Respiratory and feeding problems complicated the early neonatal course. Long-term follow-up was available for five patients (mean age of 33.2 months). Asthma, recurrent pulmonary infections, feeding problems, gastroesophageal reflux and failure to thrive were the major problems. CONCLUSIONS: Respiratory and feeding problems were the most common neonatal and long-term medical management issues. Parents need to be counseled prenatally about the probability of multiple surgeries and long hospitalization following birth.

    Title Scapular Rotation in Swimmers with and Without Impingement Syndrome: Practice Effects.
    Date October 2004
    Journal Medicine and Science in Sports and Exercise
    Excerpt

    PURPOSE: The purpose of this study was to examine the effects of a normal swim practice on the scapular kinematics of swimmers with impingement syndrome and healthy swimmers. METHODS: Twenty swimmers with no known shoulder pathology and 20 swimmers with shoulder impingement syndrome participated in this study. Shoulder strength measurements were made with a hand-held dynamometer. Static scapular upward rotation was measured with an inclinometer with the arm at rest, and at 45, 90, and 135 degrees of humeral elevation. Measurements were made pre- and postswim training. RESULTS: There were no differences in baseline measurements of kinematics between the two groups. After swimming, both groups experienced muscle fatigue as indicated by a significant reduction in force generation. Although swimming practice resulted in no significant differences in scapular kinematics for the healthy swimmers, there were significant decreases in scapular upward rotation in subjects with shoulder impingement. CONCLUSIONS: Abnormal scapular kinematics in swimmers with impingement syndrome may only be observed after an intense swim practice. The examination of swimmers immediately after swimming may provide more information regarding impingement syndrome than a typical clinical exam.

    Title Swimming Gaits, Passive Drag and Buoyancy of Diving Sperm Whales Physeter Macrocephalus.
    Date August 2004
    Journal The Journal of Experimental Biology
    Excerpt

    Drag and buoyancy are two primary external forces acting on diving marine mammals. The strength of these forces modulates the energetic cost of movement and may influence swimming style (gait). Here we use a high-resolution digital tag to record depth, 3-D orientation, and sounds heard and produced by 23 deep-diving sperm whales in the Ligurian Sea and Gulf of Mexico. Periods of active thrusting versus gliding were identified through analysis of oscillations measured by a 3-axis accelerometer. Accelerations during 382 ascent glides of five whales (which made two or more steep ascents and for which we obtained a measurement of length) were strongly affected by depth and speed at Reynold's numbers of 1.4-2.8x10(7). The accelerations fit a model of drag, air buoyancy and tissue buoyancy forces with an r(2) of 99.1-99.8% for each whale. The model provided estimates (mean +/- S.D.) of the drag coefficient (0.00306+/-0.00015), air carried from the surface (26.4+/-3.9 l kg(-3) mass), and tissue density (1030+/-0.8 kg m(-3)) of these five animals. The model predicts strong positive buoyancy forces in the top 100 m of the water column, decreasing to near neutral buoyancy at 250-850 m. Mean descent speeds (1.45+/-0.19 m s(-1)) were slower than ascent speeds (1.63+/-0.22 m s(-1)), even though sperm whales stroked steadily (glides 5.3+/-6.3%) throughout descents and employed predominantly stroke-and-glide swimming (glides 37.7+/-16.4%) during ascents. Whales glided more during portions of dives when buoyancy aided their movement, and whales that glided more during ascent glided less during descent (and vice versa), supporting the hypothesis that buoyancy influences behavioural swimming decisions. One whale rested at approximately 10 m depth for more than 10 min without fluking, regulating its buoyancy by releasing air bubbles.

    Title Abnormal Umbilical Cord Doppler Sonograms May Predict Impending Demise in Fetuses with Sacrococcygeal Teratoma. A Report of Two Cases.
    Date July 2004
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To identify factors predictive of fetal demise in fetuses with sacrococcygeal teratoma (SCT). METHOD: The recent management of monochorionic twins discordant for a large SCT and a singleton with a large SCT was reviewed. RESULTS: Serial fetal echocardiography and ultrasonography with Doppler flow measurements documented rapid growth of the SCT in both cases with a relatively modest increase in combined cardiac output. No placentomegaly or hydrops was observed at any time. In both fetuses with SCT, evolution of abnormal umbilical artery waveforms was observed with the ultimate development of reversed end-diastolic umbilical arterial flow that was followed by sudden fetal demise. CONCLUSION: Death in these 2 fetuses with large SCTs in the absence of placentomegaly/hydrops or hemodynamic changes suggestive of evolving high-output failure suggests a previously unrecognized mechanism of death in fetuses with large rapidly growing SCTs. In these cases, fetal demise may only be heralded by abnormal umbilical artery waveforms that progress to the premorbid observation of reversed diastolic umbilical artery blood flow. Umbilical artery waveform analysis should be closely monitored with other hemodynamic parameters in fetuses with large SCTs. In such fetuses, depending on the gestational age, abnormalities in umbilical artery waveform should be considered indications for early delivery or in utero intervention to prevent fetal demise.

    Title Abnormal Umbilical Cord Dopplers May Predict Impending Demise in Fetuses with Sacrococcygeal Teratoma. A Report of 2 Cases.
    Date June 2004
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To identify factors predictive of fetal demise in fetuses with sacrococcygeal teratoma (SCT). METHOD: The recent management of monochorionic twins discordant for a large SCT and a singleton with a large SCT were reviewed. RESULTS: Serial fetal echocardiography and ultrasonography with Doppler flow measurements documented rapid growth of the SCT in both cases with a relatively modest increase in combined cardiac output. No placentomegaly or hydrops was observed at any time. In both fetuses with SCT, evolution of abnormal umbilical artery waveforms was observed with the ultimate development of reversed end-diastolic umbilical arterial flow that was followed by sudden fetal demise. CONCLUSION: Death in these 2 fetuses with large SCTs in the absence of placentomegaly/hydrops or hemodynamic changes suggestive of evolving high-output failure suggests a previously unrecognized mechanism of death in fetuses with large rapidly growing SCTs. In these cases, fetal demise may only be heralded by abnormal umbilical artery waveforms that progress to the premorbid observation of reversed diastolic umbilical artery blood flow. Umbilical artery waveform analysis should be closely monitored with other hemodynamic parameters in fetuses with large SCTs. In such fetuses, depending on the gestational age, abnormalities in umbilical artery waveform should be considered indications for early delivery or in utero intervention to prevent fetal demise.

    Title Racial Differences in Survival Among Men with Prostate Cancer and Comorbidity at Time of Diagnosis.
    Date June 2004
    Journal American Journal of Public Health
    Excerpt

    OBJECTIVES: This study evaluated the effect of comorbidity at diagnosis on racial differences in survival among men with prostate cancer. METHODS: Clinical and demographic data were abstracted from records of 864 patients diagnosed at 4 Chicago area hospitals between 1986 and 1990. Comorbidity was scored on the basis of clinical information in the Charlson index. Cause-specific relative mortality adjusted for age, stage, differentiation, and treatment was compared across Charlson scores with Cox proportional hazards functions. RESULTS: Blacks had significantly greater mortality from prostate cancer and other causes (vs Whites, relative risk [95% confidence interval] = 1.84 [1.22, 2.79] and 1.69 [1.33, 2.29], respectively; P <.001). However, differences disappeared as initial comorbidity increased (1.75 [1.33, 2.31] vs 0.90 [0.59, 1.29] for scores = 0 and > or =5, respectively). CONCLUSIONS: Absence of a significant preexisting medical diagnosis is associated with a higher risk for excess mortality among Black men diagnosed with prostate cancer.

    Title Right Congenital Diaphragmatic Hernia: Prenatal Assessment and Outcome.
    Date June 2004
    Journal Journal of Pediatric Surgery
    Excerpt

    PURPOSE: To understand the natural history of right congenital diaphragmatic hernia (CDH), the authors retrospectively reviewed 27 cases of right CDH that presented for prenatal evaluation or postnatal treatment. METHODS: Between 1995 and September 2002, a total of 194 cases of fetal CDH were evaluated and included 22 right-sided defects. The authors reviewed prenatal diagnostic studies (ultrasound scan, magnetic resonance imaging [MRI] echocardiography) and pre- and postnatal outcomes in these 22 cases of right CDH. Five additional cases of right CDH without a prenatal diagnosis were reviewed. RESULTS: The mean gestational age at evaluation was 26.1 weeks. The lung area to head circumference ratio (LHR) ranged from 0.32 to 2.5. In all cases, the fetal liver was herniated into the right chest. Associated anomalies were common. There were no karyotype abnormalities (17 of 22 tested). There were 4 terminations. Nine of the 18 (50%) continuing pregnancies had polyhydramnios, premature rupture of membranes, or preterm labor. The mean gestational age at birth was 36.8 weeks. One patient underwent tracheal occlusion at 27 weeks, and 2 patients died before postnatal repair. Overall survival rate (22 prenatal plus 5 postnatal diagnoses) was 19 of 27 (70%). Postnatal survival rate was 19 of 23 (83%). A Gore-tex (W. L. Gore and Associates, Flagstaff, AZ) patch was utilized in 14 of 21 neonates undergoing surgery. Twelve of 23 (52%) required extracorporeal membrane oxygenation (ECMO) with a 75% survival rate. Significant morbidity occurred in 10 of 19 survivors and included neurologic sequelae in 6 of 19 (32%). CONCLUSIONS: MRI was helpful in the determination of liver position and confirmation of diagnosis. The high incidence of preterm complications, frequent need for ECMO, and high prevalence of comorbidities are indicative of the severity of this CDH population and warrant close prenatal surveillance and delivery at a tertiary care center with ECMO capability.

    Title Sacrococcygeal Teratoma: Prenatal Assessment, Fetal Intervention, and Outcome.
    Date June 2004
    Journal Journal of Pediatric Surgery
    Excerpt

    PURPOSE: To understand the natural history and define indications for fetal intervention in sacrococcygeal teratoma (SCT), the authors reviewed all cases of fetal SCT presenting for evaluation. METHODS: Prenatal diagnostic studies including ultrasound scan, magnetic resonance imaging (MRI), echocardiography and pre- and postnatal outcomes were reviewed in 30 cases of SCT that presented between September 1995 and January 2003. RESULTS: The mean gestational age (GA) at presentation was 23.9 weeks (range, 19 to 38.5) with 3 sets of twins (10%). Overall outcomes included 4 terminations, 5 fetal demises, 7 neonatal deaths, and 14 survivors. Significant obstetric complications occurred in 81% of the 26 continuing pregnancies: polyhydramnios (n = 7), oligohydramnios (n = 4), preterm labor (n = 13), preeclampsia (n = 4), gestational diabetes (n = 1), HELLP syndrome (n = 1), and hyperemesis (n = 1). Fetal intervention included cyst aspiration (n = 6), amnioreduction (n = 3), amnioinfusion (n = 1), and open fetal surgical resection (n = 4). Indications for cyst aspiration and amnioreduction were maternal discomfort, preterm labor, and prevention of tumor rupture at delivery. Although 15 SCTs were solid causing risk for cardiac failure, only 4 fetuses met criteria for fetal debulking based on ultrasonographic and echocardiographic evidence of impending high output failure and favorable anatomy at 21, 23.6, 25, and 26 weeks' gestation. Intraoperative events included maternal blood transfusion (n = 1), fetal blood transfusion (n = 2), chorioamniotic membrane separation (n = 2), and fetal arrest requiring successful cardiopulmonary resuscitation (CPR) (n = 1). In the fetal resection group, 3 of 4 survived with mean GA at delivery of 29 weeks (range, 27.6 to 31.7 weeks), mean birth weight of 1.3 kg, hospital stay ranging from 16 to 34 weeks, and follow-up ranging from 20 months to 6 years. Postnatal complications in the fetal surgery group included neonatal death (n = 1, secondary to premature closure of ductus arteriosus with cardiac failure), embolic event (n = 1, resulting in unilateral renal agenesis, jejunal atresia), chronic lung disease (n = 1), and tumor recurrence (n = 1). CONCLUSIONS: For fetal SCT, the rapidity at which cardiac compromise can develop and the high incidence of obstetric complications warrant close prenatal surveillance. Amnioreduction, cyst aspiration, and surgical debulking are potentially life-saving interventions.

    Title Locked Nucleic Acid (lna) Single Nucleotide Polymorphism (snp) Genotype Analysis and Validation Using Real-time Pcr.
    Date May 2004
    Journal Nucleic Acids Research
    Excerpt

    With an increased emphasis on genotyping of single nucleotide polymorphisms (SNPs) in disease association studies, the genotyping platform of choice is constantly evolving. In addition, the development of more specific SNP assays and appropriate genotype validation applications is becoming increasingly critical to elucidate ambiguous genotypes. In this study, we have used SNP specific Locked Nucleic Acid (LNA) hybridization probes on a real-time PCR platform to genotype an association cohort and propose three criteria to address ambiguous genotypes. Based on the kinetic properties of PCR amplification, the three criteria address PCR amplification efficiency, the net fluorescent difference between maximal and minimal fluorescent signals and the beginning of the exponential growth phase of the reaction. Initially observed SNP allelic discrimination curves were confirmed by DNA sequencing (n = 50) and application of our three genotype criteria corroborated both sequencing and observed real-time PCR results. In addition, the tested Caucasian association cohort was in Hardy-Weinberg equilibrium and observed allele frequencies were very similar to two independently tested Caucasian association cohorts for the same tested SNP. We present here a novel approach to effectively determine ambiguous genotypes generated from a real-time PCR platform. Application of our three novel criteria provides an easy to use semi-automated genotype confirmation protocol.

    Title North Atlantic Right Whales (eubalaena Glacialis) Ignore Ships but Respond to Alerting Stimuli.
    Date April 2004
    Journal Proceedings. Biological Sciences / The Royal Society
    Excerpt

    North Atlantic right whales were extensively hunted during the whaling era and have not recovered. One of the primary factors inhibiting their recovery is anthropogenic mortality caused by ship strikes. To assess risk factors involved in ship strikes, we used a multi-sensor acoustic recording tag to measure the responses of whales to passing ships and experimentally tested their responses to controlled sound exposures, which included recordings of ship noise, the social sounds of conspecifics and a signal designed to alert the whales. The whales reacted strongly to the alert signal, they reacted mildly to the social sounds of conspecifics, but they showed no such responses to the sounds of approaching vessels as well as actual vessels. Whales responded to the alert by swimming strongly to the surface, a response likely to increase rather than decrease the risk of collision.

    Title Sibpair Studies Implicate Chromosome 18 in Essential Hypertension.
    Date April 2004
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    Interest in chromosome 18 in essential hypertension comes from comparative mapping of rat blood pressure quantitative trait loci (QTL), familial orthostatic hypotensive syndrome studies, and essential hypertension pedigree linkage analyses indicating that a locus or loci on human chromosome 18 may play a role in hypertension development. To further investigate involvement of chromosome 18 in human essential hypertension, the present study utilized a linkage scan approach to genotype twelve microsatellite markers spanning human chromosome 18 in 177 Australian Caucasian hypertensive (HT) sibling pairs. Linkage analysis showed significant excess allele sharing of the D18S61 marker when analyzed with SPLINK (P = 0.00012), ANALYZE (Sibpair) (P = 0.0081), and also with MAPMAKER SIBS (P = 0.0001). Similarly, the D18S59 marker also showed evidence for excess allele sharing when analyzed with SPLINK (P = 0.016), ANALYZE (Sibpair) (P = 0.0095), and with MAPMAKER SIBS (P = 0.014). The adenylate cyclase activating polypeptide 1 gene (ADCYAP1) is involved in vasodilation and has been co-localized to the D18S59 marker. Results testing a microsatellite marker in the 3' untranslated region of ADCYAP1 in age and gender matched HT and normotensive (NT) individuals showed possible association with hypertension (P = 0.038; Monte Carlo P = 0.02), but not with obesity. The present study shows a chromosome 18 role in essential hypertension and indicates that the genomic region near the ADCYAP1 gene or perhaps the gene itself may be implicated. Further investigation is required to conclusively determine the extent to which ADCYAP1 polymorphisms are involved in essential hypertension.

    Title Prenatal Ultrasound Guided Percutaneous Shunts for Obstructive Uropathy and Thoracic Disease.
    Date January 2004
    Journal Seminars in Pediatric Surgery
    Excerpt

    The authors reviewed the status of closed ultrasound-guided fetal therapy using a pigtail shunt to create vesicoamniotic or thoracoamniotic decompression of the fluid-filled space. This review includes published and textbook reports of in utero therapy for bladder obstruction, pleural effusion, and macrocystic adenomatoid malformation from 1985 through 2002. For fetuses affected by lower urinary tract obstruction, the key component is identifying those fetuses that have retained renal function and are most likely to benefit from in utero shunting. This good prognosis group has been shown to have improved survival rate and a lower incidence of renal failure. Complications of fetal loss are estimated at 5% owing to the shunt procedure, and the risk of shunt displacement varies from 30% to 50%. Hydrops secondary to primary PE has been shown to be associated with low fetal and neonatal survival at 21% to 23%. Treatment by thoracoamniotic shunting increases survival rate to 75%. The fetus with a macrocystic CCAM and secondary hydrops should be considered a candidate for thoracoamniotic shunt to decrease CCAM volume, reverse hydrops, and improve survival rate. Thoracoamniotic shunt and thoracocentesis pregnancy loss risks for pleural effusion (PE) and macrocystic adenomatoid malformation of the lung (CCAM) are 5% and 0.5% to 1.0%, respectively.

    Title Chorioamniotic Membrane Separation Following Open Fetal Surgery: Pregnancy Outcome.
    Date December 2003
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To review the incidence of posthysterotomy chorioamniotic membrane separation and delivery outcome following open fetal surgery [myelomeningocele (MMC); cystic adenomatoid malformation (CCAM); congenital diaphragmatic hernia (CDH); sacrococcygeal teratoma (SCT)]. STUDY DESIGN: Retrospective review of a maternal population undergoing open fetal surgery at a single tertiary level program (1998-2001) following the initiation of close postoperative ultrasound follow-up for membrane separation. Onset of membrane separation was coded as not present (NP), immediate (<2 weeks) or delayed (>2 weeks) from day of surgery. RESULTS: Fifty-three charts were reviewed: MMC 43, CCAM 7, CDH 1, and SCT 2. In the MMC group there were 26 NP, 8 immediate, and 9 delayed. Preterm labor occurred in 4 patients with only 2 having had membrane separation. Risk of membrane separation is increased for surgery done at less than 23 weeks gestation (p < 0.005). Delay from MMC surgery to delivery was 11.0, 9.8, 12.0 weeks for NP, immediate, and delay, respectively. In the MMC group, there were 3 neonatal deaths (NND) at 9, 9, and 21 days post surgery (PROM/PTL; chorioamnionitis, PROM/PTL, respectively). No membrane separation was present in the CCAM, CDH, and SCT cases. CONCLUSIONS: (1) Membrane separation was significantly more likely to occur if surgery was performed prior to 23 weeks. (2) Membrane separation post hysterotomy (17/50 = 34%) may be associated with an increased risk of PROM but not delivery before 30 weeks gestation. (3) Delivery prior to 33 weeks gestation for MMC groups was 12/43 (28%) with 3 NND (7%). (4) Elective delivery at 36-37 weeks gestation was possible for 43% of the fetal surgery population.

    Title Fetal Surgery for Myelomeningocele.
    Date December 2003
    Journal Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery
    Excerpt

    INTRODUCTION: Although in utero treatment of myelomeningocele shows promise in decreasing the morbidity of this disease, the risks to the fetus are significant, and the benefits are unproven. TRIAL: The upcoming trial represents one of the few times that the pediatric neurosurgical community has come together to test a new procedure.

    Title An Investigation of the 5-ht2c Receptor Gene As a Migraine Candidate Gene.
    Date November 2003
    Journal American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics
    Excerpt

    Migraine is a common complex disorder, currently classified into two main subtypes, migraine with aura (MA) and migraine without aura (MO). The strong preponderance of females to males suggests an X-linked genetic component. Recent studies have identified an X chromosomal susceptibility region (Xq24-q28) in two typical migraine pedigrees. This region harbours a potential candidate gene for the disorder, the serotonin receptor 2C (5-HT(2C)) gene. This study involved a linkage and association approach to investigate two single nucleotide variants in the 5-HT(2C) gene. In addition, exonic coding regions of the 5-HT(2C) gene were also sequenced for mutations in X-linked migraine pedigrees. Results of this study did not detect any linkage or association, and no disease causing mutations were identified. Hence, results for this study do not support a significant role of the 5-HT(2C) gene in migraine predisposition.

    Title Fetal Myelomeningocele Repair: Short-term Clinical Outcomes.
    Date October 2003
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: The study was undertaken to evaluate short-term clinical outcomes with antenatal myelomeningocele (MMC) repair. STUDY DESIGN: Retrospective review of 50 fetuses that underwent open fetal MMC closure was performed. Inclusion criteria included less than 26 weeks' gestation, thoracic to S1 level defect, absent clubfoot deformity, Arnold-Chiari malformation, ventriculomegaly less than 17 mm, normal karyotype, and no other anomalies. RESULTS: Perinatal survival was 94% (47/50 fetuses). Mean age at delivery was 34 weeks 3 days. All fetuses demonstrated reversal of hindbrain herniation. Forty-three percent of the 50 fetuses have required ventriculoperitoneal shunting compared with 100% thoracic, 88% lumbar, and 68% sacral (85% overall) in 297 historic controls. Better-than-predicted leg function was seen in 57% of thoracic and lumbar level lesion patients. CONCLUSION: Early experience with fetal MMC repair suggests a decreased need for ventriculoperitoneal shunting, arrest or slowing of progressive ventriculomegaly, and consistent resolution of hindbrain herniation. However, further long-term follow-up is needed to evaluate neurodevelopment and bladder and bowel function.

    Title In Utero Limb Salvage: Fetoscopic Release of Amniotic Bands for Threatened Limb Amputation.
    Date October 2003
    Journal Journal of Pediatric Surgery
    Excerpt

    The natural history of extremity amniotic band syndrome (ABS) is a progression to deformity or amputation. Fetoscopic laser release of amniotic bands in extremity ABS offers the potential to prevent limb amputation. The authors report on 2 patients with isolated extremity ABS who underwent fetoscopic release. Both patients had isolated extremity ABS with compromised extremity perfusion and no other significant structural abnormality diagnosed sonographically. The first patient underwent fetoscopic release of bands of the left wrist, and the second patient underwent lysis of bands around the right wrist and an unsuspected band around the right lower extremity. Both patients had restoration of blood flow by color Doppler to the affected extremity. There were no perioperative complications. In select patients with isolated extremity ABS, early fetoscopic release may prevent amputation and allow improved limb development.

    Title Congenital High Airway Obstruction Syndrome: Natural History and Management.
    Date October 2003
    Journal Journal of Pediatric Surgery
    Excerpt

    BACKGROUND: Congenital high airway obstruction syndrome (CHAOS) is a life-threatening condition with a poorly understood natural history. METHODS: A retrospective review of five patients with CHAOS between 1997 and 2002 was performed. RESULTS: All fetuses had large echogenic lungs, dilated airways, inverted diaphragms, and massive ascites. One fetus with a laryngeal cyst was terminated at 22 weeks. A twin fetus with findings suggestive of a tracheal web had progressive hydrops, which led to fetal demise. The remaining 3 patients delivered via the ex utero intrapartum treatment (EXIT) procedure survived. The first patient tolerated progressive hydrops for 12 weeks in utero. He had tracheal atresia but underwent laryngotracheoplasty successfully. He is the first long-term CHAOS survivor and is speaking at 5 years of age. The 2 patients with relatively stable lung volumes prenatally have laryngeal atresia with a pinpoint posterior laryngeal fistula. Their postnatal clinical courses were much more benign than the first survivor. CONCLUSIONS: The prenatal natural history and postnatal course of CHAOS depends on whether the airway obstruction is complete. The EXIT procedure offers the potential for salvage of this otherwise lethal condition. Hydrops may be well tolerated prenatally for weeks with potential resolution if airway fistulization is present.

    Title History of Fetal Diagnosis and Therapy: Children's Hospital of Philadelphia Experience.
    Date September 2003
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Since its inception in 1995, the mission of the Center for Fetal Diagnosis and Treatment at the Children's Hospital of Philadelphia (CHOP) has been to provide comprehensive, multidisciplinary expertise in all facets of prenatal diagnosis, reproductive genetics, and prenatal, perinatal, and postnatal treatment for abnormal fetuses. Most of the authors were trained and/or served on faculty at centers in San Francisco (N.S.A., A.W.F., T.M.C., L.J.H.) or Detroit (A.W.F, M.P.J.). Accurate prenatal detection by serial sonographic study and the development of ultrafast magnetic resonance imaging (MRI) scanners has permitted delineation of the natural history of anatomic malformations. Definition of the pathophysiological features that affect clinical outcome and formulation of management based on prognosis has allowed families to make informed decisions. Outcomes have been improved through carefully planned and coordinated perinatal management. In some cases of life-threatening or severely debilitating defects, prenatal surgery has been offered.

    Title Fetoscopic Surgery.
    Date August 2003
    Journal Clinical Obstetrics and Gynecology
    Title Discovery of Allosteric Potentiators for the Metabotropic Glutamate 2 Receptor: Synthesis and Subtype Selectivity of N-(4-(2-methoxyphenoxy)phenyl)-n-(2,2,2- Trifluoroethylsulfonyl)pyrid-3-ylmethylamine.
    Date August 2003
    Journal Journal of Medicinal Chemistry
    Excerpt

    This report describes recently discovered novel allosteric modulators of metabotropic glutamate2 (mGlu2) receptors. These pyridylmethylsulfonamides (e.g., 3) potentiate glutamate, shifting agonist potency by 2-fold. This effect was specific for mGlu2 (vs mGlu1,3-8 receptors). Also, 3 failed to potentiate a chimeric mGlu2/1 receptor, demonstrating the mGlu2 transmembrane region's critical involvement. In a fear-potentiated startle model, 3 showed anxiolytic activity that was prevented by mGlu2/3 antagonist pretreatment. Thus, these pyridylmethylsulfonamides represent the first mGlu2 receptor potentiators discovered.

    Title Comment on "single Crystals of Single-walled Carbon Nanotubes Formed by Self-assembly".
    Date June 2003
    Journal Science (new York, N.y.)
    Title The Wayne State Experience.
    Date April 2003
    Journal Fetal Diagnosis and Therapy
    Title Group Ii Metabotropic Glutamate Receptor Modulation of Doi-induced C-fos Mrna and Excitatory Responses in the Cerebral Cortex.
    Date March 2003
    Journal Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
    Excerpt

    Recent studies have demonstrated that the hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) enhances glutamatergic transmission in the prefrontal cortex. This increase can be suppressed by metabotropic glutamate2/3 (mGlu2/3) receptor activation. In addition to enhancing glutamatergic transmission, DOI increases cortical c-fos expression. We tested if a reduction in glutamate release produced by mGlu2/3 receptor activation attenuates DOI-induced c-fos expression in the cortex. Similar to previous studies, DOI produced a robust increase in c-fos mRNA throughout the cortex, including the prefrontal, frontoparietal, and somatosensory regions. Pretreatment with the mGlu2/3 agonist LY379268 attenuated the DOI-induced increase in the prefrontal cortex. This suppression was blocked by the mGlu2/3 antagonist LY341495. In contrast, the DOI-induced increase in c-fos mRNA in the frontoparietal and somatosensory cortex was unaffected by the mGlu2/3 agents. These findings suggest that Group II metabotropic glutamate receptor agonists are capable of modulating postsynaptic function preferentially in the limbic cortex under conditions of enhanced glutamate release.

    Title The Implications of Unfulfilled Expectations and Perceived Pressure to Attend the Birth on Men's Stress Levels Following Birth Attendance: a Longitudinal Study.
    Date February 2003
    Journal Journal of Psychosomatic Obstetrics and Gynaecology
    Excerpt

    Men's stress and their experiences of reproduction have yet to be fully explored. This study aims to examine the subjective stress experienced by men during their partner's pregnancy, at the time of the birth and six weeks postpartum by means of a longitudinal study of 53 men's reproductive experience. Further, it aims to examine the role birth attendance, unfulfilled expectations and perceived pressure to attend the birth have on levels of stress. Men were measured on the Impact of Event Scale three times during the pregnancy, at the time of the birth and six weeks postpartum. Findings indicate that compared to non-psychiatric norms, overall levels of stress were elevated during the pregnancy, at birth and postpartum. The highest levels of stress were found at the time of the birth in the men who were in birth attendance. Stress levels were particularly high amongst men who felt they did not fulfill their role expectation, or they perceived pressure to be present at the birth. Confirming findings from phenomenological studies, there appears to be some confusion as to the nature and purpose of men's presence at childbirth. Expectant fathers may not anticipate the psychological and emotional realities of childbirth/becoming a father and there remains a possibility that raised stress following childbirth may impact on father/child bonding.

    Title Fetal Therapy: State of the Art.
    Date February 2003
    Journal Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine
    Excerpt

    OBJECTIVE: To review our experience with the use of sonography in evaluating potential candidates for in utero fetal therapy performed at The Center for Fetal Diagnosis and Treatment at The Children's Hospital of Philadelphia. METHODS: This review article was designed to discuss open hysterotomy for the 4 fetal surgical procedures that have been performed at our institution. The procedures included surgical repair of myelomeningocele, resection of sacrococcygeal teratoma in fetuses with nonimmune hydrops, resection of an enlarging congenital cystic adenomatoid malformation that is not amenable to thoracoamniotic shunting, and tracheal clip occlusion for severe left congenital diaphragmatic hernia. RESULTS: For each surgical procedure, the use of sonography in the prenatal diagnosis of the congenital anomaly was detailed, as were indications for surgery and surgical procedures, postoperative monitoring and finally delivery, postnatal treatment, and long-term follow-up. Three of the procedures have been reasonably successful with rather dramatic results in some cases such that these techniques are still being performed. The 1 exception was open hysterotomy for the tracheal clip procedure for congenital diaphragmatic hernia, which has been abandoned. CONCLUSIONS: Fetal therapy is a rapidly evolving specialty, which is being practiced at several centers in this country. Sonography is an integral part of this specialty practice and has been used extensively in the diagnosis of some congenital anomalies that have debilitating or lethal consequences for the fetus. Technologic improvements in both sonography and magnetic resonance imaging have assisted tremendously in the many advances herein reported in the diagnosis and treatment of the above-described 4 congenital anomalies.

    Title Fetal Therapy.
    Date January 2003
    Journal Best Practice & Research. Clinical Obstetrics & Gynaecology
    Excerpt

    Over the past 40 years, a small but increasing number of fetal genetic and congenital anomalies has become amenable to in utero treatment. Successful fetal therapies have included open procedures for congenital diaphragmatic hernia, cystadenomatoid malformation of the lung and saccrococygeal teratoma, shunts for uropathies and thoracic fluids, pharmacological therapies for congenital adrenal hyperplasia and neural tube defect prevention, and the stem cell treatment of severe combined immunodeficiency disorder.

    Title Magnetic Resonance Imaging of Fetal Urinoma.
    Date January 2003
    Journal Urology
    Excerpt

    Extrarenal collections of urine have long been associated with obstructive uropathy and may preserve renal function by acting as a "popoff" valve. Although urinary extravasation manifested as urinary ascites carries a favorable prognosis, perinephric urinomas occurring prenatally are associated with poor renal function in most cases. We report the case of a baby girl with a urinoma diagnosed by fetal magnetic resonance imaging and discuss the significance of this radiologic finding.

    Title Inhibition of Group I Metabotropic Glutamate Receptor Responses in Vivo in Rats by a New Generation of Carboxyphenylglycine-like Amino Acid Antagonists.
    Date December 2002
    Journal Neuroscience Letters
    Excerpt

    A series of novel group I metabotropic glutamate receptor (mGlu) antagonists have been designed on the basis of the 4-carboxyphenylglycine pharmacophore. The compounds are either mGlu1 receptor selective or equipotent for both mGlu1 and mGlu5 receptors and have IC(50) values ranging from 1 to 30 microM determined by phosphoinositide hydrolysis (PI) assay in vitro. All the compounds produced dose-dependent inhibition of group I mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced limbic seizure responses in mice with ED(50) values ranging from 9 nmol for LY393053 to 138 nmol for LY339840 after intracerebroventricular injection and were more potent than the mGlu1 receptor antagonist 1-aminoindan-1,5-dicarboxylic acid (ED(50)=477 nmol). Further antagonist actions were also demonstrated in a model of (RS)-DHPG-induced PI hydrolysis in vivo such that LY367385 and the active cis isomer of LY393053 produced dose-dependent inhibition of PI responses in both cerebellum and hippocampus. Cis LY393053 also inhibited hippocampal PI responses when administered intraperitoneally at a dose of 30 mg/kg. These compounds define a new series of group I mGlu receptor antagonists which may serve as useful experimental tools.

    Title Modulation of Stress-induced and Stimulated Hyperprolactinemia with the Group Ii Metabotropic Glutamate Receptor Selective Agonist, Ly379268.
    Date December 2002
    Journal Neuropharmacology
    Excerpt

    It is well recognized that glutamate is an integral excitatory neurotransmitter in the neuroendocrine control of several hormonal factors. While the ability of pharmacological agents acting at ionotropic glutamate receptors to modulate the levels of serum prolactin levels has been investigated, there have been few reports of the effects mediated by the G-protein coupled, metabotropic glutamate (mGlu) receptors. The present work was undertaken to investigate the role of the Group II mGlu receptors, mGlu2 and mGlu3 in the regulation of serum polactin levels. LY379268, a Group II selective agonist, did not alter basal levels of circulating prolactin in young (36-40 day old) male rats. However, when an immobilization stress-induced hyperprolactinemia was examined, 10 mg/kg s.c. of LY379268 significantly lowered serum prolactin levels. Similarly, pretreatment with LY379268 was able to reverse the hyperprolactinemia induced with the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine (aMPT). This inhibition of hyperprolactinemia could be prevented by pretreatment with LY341495, a Group II mGlu receptor antagonist. The Group II antagonist alone had no effect on either basal nor stimulated prolactin levels. The agonist LY379268 was able to prevent the transient hyperprolactinemia associated with stimulation of serotonin 5-HT2A receptors by 2,5-dimethoxy-4-iodoamphetamine (DOI), but did not alter the high levels of circulating prolactin induced with the D2 antagonist, haloperidol. When treatment with LY379268 was delayed until 1 h after aMPT, a time demonstrated to show a full effect of aMPT on serum prolactin levels, the Group II agonist was similarly able to reverse hyperprolactinemia, suggesting LY379268 did not act by preventing the partial catecholamine depletion by aMPT. Similarly, high doses of amphetamine, a dopamine (DA) releaser, were able to reverse the aMPT-induced hyperprolactinemia, consistent with sufficient levels of dopamine remaining after aMPT treatment to modulate prolactin levels. LY379268 did not alter the hyperprolactinemia seen in estrogen-primed, ovariectomized female rats. Taken together the results indicate that stimulation of mGlu2/3 has an indirect inhibitory action on pituitary prolactin release. It is speculated that disinhibition of tubero-infundibular DA release by presynaptic Group II mGlu receptors located on inhibitory inputs to the arcuate hypothalamic nucleus is a possible explanation for the findings.

    Title Apocalyptic Thinking, Autonomy, and Sociotropy.
    Date August 2002
    Journal Psychological Reports
    Excerpt

    As the millennium approached there was a unique opportunity to examine beliefs about impending apocalyptic events. In March, 1998 60 English participants, 20 to 35 years of age, including 20 Jehovah's Witnesses, 20 Roman Catholics, and 20 Methodists, completed a four-dimension scale of Positive and Negative Autonomy and Positive and Negative Sociotropy and a questionnaire, Apocalyptic Thinking, on the millennium containing questions on apocalyptic beliefs. The aim of the study was to investigate the apocalyptic beliefs of a number of Christian denominations and examine the relationship between scores on apocalyptic thinking about the millennium and group cohesion. Jehovah's Witnesses scored highest on all scales except Positive Autonomy, and the Catholics had higher Negative Sociotropy and Apocalyptic Thinking scores than the Methodists. Negative Sociotropy scores correlated positively with Apocalyptic Thinking scores for all groups. These data suggest significant positive relationship between these Christian endorsements of the likelihood of apocalyptic events at the millennium and the extent to which they perceive nonmembers of their denomination as 'outsiders'.

    Title Influence of Congenital Heart Disease on Survival in Children with Congenital Diaphragmatic Hernia.
    Date August 2002
    Journal The Journal of Pediatrics
    Excerpt

    OBJECTIVE: We sought to assess outcome in patients with CDH and HD to determine if LHR is also predictive of outcome in this subset of patients. STUDY DESIGN: We carried out a retrospective review (April 1996-October 2000) of patients with isolated CDH (n = 143, 82.2%) and patients with HD (n = 31, 17.8%) to determine the incidence of additional anomalies, survival to term, CDH repair, cardiac repair, and survival to discharge. Survival based on LHR was analyzed in a subset of fetuses. RESULTS: The risk of death from birth to last follow-up was 2.9 times higher for patients with CDH plus HD than for patients with CDH alone (P <.0001). Of 11 patients with CDH plus HD who had CDH repair (5 of whom also had HD repair), 5 survived. All 10 patients with an LHR <1.2 died; 3 of 6 with an LHR >1.2 survived (Fisher exact test, P =.04). CONCLUSION: Heart disease remains a significant risk factor for death in infants with CDH. The LHR helps predict survival in this high-risk group of patients.

    Title The Natural History of Prenatally Diagnosed Conjoined Twins.
    Date April 2002
    Journal Journal of Pediatric Surgery
    Excerpt

    BACKGROUND/PURPOSE: Accurate prenatal diagnosis of complex anatomic connections and associated anomalies has only been possible recently with the use of ultrasonography, echocardiography, and fetal magnetic resonance imaging (MRI). To assess the impact of improved antenatal diagnosis in the management and outcome of conjoined twins, the authors reviewed their experience with 14 cases. METHODS: A retrospective review of prenatally diagnosed conjoined twins referred to our institution from 1996 to present was conducted. RESULTS: In 14 sets of conjoined twins, there were 10 thoracoomphalopagus, 2 dicephalus tribrachius dipus, 1 ischiopagus, and 1 ischioomphalopagus. The earliest age at diagnosis was 9 weeks' gestation (range, 9 to 29; mean, 20). Prenatal imaging with ultrasonography, echocardiography, and ultrafast fetal MRI accurately defined the shared anatomy in all cases. Associated anomalies included cardiac malformations (11 of 14), congenital diaphragmatic hernia (4 of 14), abdominal wall defects (2 of 14), and imperforate anus (2 of 14). Three sets of twins underwent therapeutic abortion, 1 set of twins died in utero, and 10 were delivered via cesarean section at a mean gestational age of 34 weeks. There were 5 individual survivors in the series after separation (18%). In one case, in which a twin with a normal heart perfused the cotwin with a rudimentary heart, the ex utero intrapartum treatment procedure (EXIT) was utilized because of concern that the normal twin would suffer immediate cardiac decompensation at birth. This EXIT-to-separation strategy allowed prompt control of the airway and circulation before clamping the umbilical cord and optimized control over a potentially emergent situation, leading to survival of the normal cotwin. In 2 sets of twins in which each twin had a normal heart, tissue expanders were inserted before separation. CONCLUSIONS: Advances in prenatal diagnosis allow detailed, accurate evaluations of conjoined twins. Careful prenatal studies may uncover cases in which emergent separation at birth is lifesaving.

    Title The Exit Procedure: Experience and Outcome in 31 Cases.
    Date April 2002
    Journal Journal of Pediatric Surgery
    Excerpt

    BACKGROUND: The EXIT (ex utero intrapartum treatment) procedure, although initially designed for reversal of tracheal occlusion in fetuses with congenital diaphragmatic hernias (CDH), has been adapted to treat a variety of fetal conditions. METHODS: A retrospective chart review of all consecutive EXIT procedures since 1996 was conducted. RESULTS: Thirty-one women underwent the EXIT procedure, with an average maternal age of 29 years (range, 20 to 38), and average gestational age of 34 weeks (range, 29 to 40). The indication was airway obstruction from fetal neck mass in 13, and reversal of tracheal occlusion from in utero clipping in 13. Singular indications included an EXIT-to-ECMO (extracorporeal membrane oxygenation) procedure for a fetus with CDH and a cardiac defect (n = 1), congenital high airway obstruction syndrome (CHAOS, n = 1), resection of a very large congenital cystic adenomatoid malformation of the lung (CCAM) on uteroplacental bypass (n = 1), unilateral pulmonary agenesis (n = 1), and thoracoomphalopagus conjoined twins. The mean duration on uteroplacental bypass (from uterine incision to umbilical cord clamping) was 30.3 plus minus 14.7 minutes (range, 8 to 66). No fetus experienced hemodynamic instability during uteroplacental bypass as recorded by fetal heart rate (FHR), pulse oximeter, and fetal echocardiography, except for one instance of reversible bradycardia from umbilical cord compression. The mean FHR and fetal saturation were 153.0 plus minus 38.5 beats per minute and 71.2% plus minus 19.9%, respectively. Five fetuses required a tracheostomy. Only 1 death occurred during an EXIT procedure because of inability to secure the airway secondary to extensive involvement by a lymphangioma. The average cord pH and pCO(2) were, respectively, 7.20 plus minus 0.11 and 63.2 plus minus 14.6. Two maternal complications occurred: bleeding from a hysterotomy site and dehiscence of an old hysterotomy scar noticed at a subsequent cesarean section. The average maternal blood loss was 848.3 plus minus 574.1 mL. CONCLUSION: The EXIT procedure was used successfully to ensure uteroplacental gas exchange and fetal hemodynamic stability during a variety of surgical procedures performed to secure the fetal airway or ensure successful transition to postnatal environment.

    Title Vesicoamniotic Shunt in a Female Fetus with the Prune Belly Syndrome.
    Date December 2001
    Journal The Journal of Urology
    Title Buoyant Balaenids: the Ups and Downs of Buoyancy in Right Whales.
    Date December 2001
    Journal Proceedings. Biological Sciences / The Royal Society
    Excerpt

    A variety of marine mammal species have been shown to conserve energy by using negative buoyancy to power prolonged descent glides during dives. A new non-invasive tag attached to North Atlantic right whales recorded swim stroke from changes in pitch angle derived from a three-axis accelerometer. These results show that right whales are positively buoyant near the surface, a finding that has significant implications for both energetics and management. Some of the most powerful fluke strokes observed in tagged right whales occur as they counteract this buoyancy as they start a dive. By contrast, right whales use positive buoyancy to power glides during ascent. Right whales appear to use their positive buoyancy for more efficient swimming and diving. However, this buoyancy may pose added risks of vessel collision. Such collisions are the primary source of anthropogenic mortality for North Atlantic right whales, whose population is critically endangered and declining. Buoyancy may impede diving responses to oncoming vessels and right whales may have a reduced ability to manoeuvre during free ascents. These risk factors can inform efforts to avoid collisions.

    Title Chromosome 17 and the Inducible Nitric Oxide Synthase Gene in Human Essential Hypertension.
    Date December 2001
    Journal Human Genetics
    Excerpt

    Essential hypertension is a common multifactorial trait that results in a significantly increased risk for heart attack and stroke. The condition has a genetic basis, although at present the number of genes is unknown. In order to identify such genes, we are utilising a linkage scanning approach using microsatellite markers and affected sibships. Here we provide evidence for the location of at least one hypertension susceptibility locus on chromosome 17. Analysis of 177 affected sibpairs gave evidence for significant excess allele sharing to D17S949 (SPLINK: P=0.0029; MAPMAKER SIBS: P=0.0033; ASPEX: P=0.0061; GENEHUNTER: P=0.0096; ANALYZE (SIBPAIR): P=0.0025) on 17q22-24, with significant allele sharing also indicated for an additional marker, D17S799 (SPLINK: P=0.025; MAPMAKER SIBS: P=0.025) located close to the centromere. Since these two genomic regions are well separated, our results indicate that there may be more than one chromosome 17 locus affecting human blood pressure. Moreover, further investigation of this chromosome, utilizing a polymorphism within the promoter of the iNOS candidate gene, NOS2A, revealed both increased allele sharing among sibpairs (SPLINK: P=0.02; ASPEX: P=0.00004) and positive association (P=0.034) of NOS2A to essential hypertension. Hence these results indicate that chromosome 17 and, more specifically, the NOS2A gene may play a role in human essential hypertension.

    Title The Rationale for in Utero Repair of Myelomeningocele.
    Date October 2001
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVES: Despite advances in prenatal diagnosis, management of fetal myelomeningocele has been limited to abortion or supportive postnatal care. The rationale for fetal repair of myelomeningocele and initial clinical outcomes are discussed. METHODS: A complete review of the literature concerning fetal myelomeningocele and repair was performed. RESULTS: While myelomeningocele is a primary embryologic disorder, neurologic damage is also secondary to progressive in utero damage to the exposed spinal cord. Animal models with midgestational coverage of the spinal defect demonstrate near normal neurologic function at term. Early clinical results suggest that fetal closure can salvage neurologic function, reverse hindbrain herniation, and diminish the need for ventriculoperitoneal shunting. CONCLUSIONS: In utero repair of myelomeningocele may improve neurologic outcomes and reduce hindbrain herniation in selected patients.

    Title Changes in Rat Serum Corticosterone After Treatment with Metabotropic Glutamate Receptor Agonists or Antagonists.
    Date September 2001
    Journal Journal of Neuroendocrinology
    Excerpt

    From previous work, it appears that glutamate can activate the hypothalamic-pituitary-adrenocortical (HPA) axis by an interaction at either ionotopic or metabotropic (G-protein coupled) receptors. For example, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD), a metabotropic glutamate (mGlu) receptor agonist, has been shown to increase the levels of serum corticosterone in rats. The present study was undertaken to further characterize which of the mGlu receptors are substantially involved in control of the HPA axis. The group I mGlu receptor agonists, 3,5-dihydroxyphenylglycine (DHPG), 1S,3R-ACPD, and 2-chloro-5-hydroxyphenylglycine (CHPG) but not the inactive isomer 1R,3S-ACPD were found to dose-dependently increase serum corticosterone 1 h after intracerebroventricular (i.c.v.) injection in male rats. The relative potency, DHPG (EC50 = 520 nmol) > 1S,3R-ACPD (1.4 micromol) = CHPG (2.7 micromol) >> 1R,3S-ACPD (>> 3 micromol) is consistent with activation of group I (mGlu1/5) receptors. The effects of DHPG were long lasting with substantial elevations in corticosterone remaining for at least 3 h. In a similar manner, the group III mGlu receptor agonists, L-AP4 (4-phosphono-2-aminobutyric acid) and L-SOP (serine-O-phosphate), were found to increase serum corticosterone levels at 1 h. In contrast, the mGlu group II selective agonists LY354740 (10 mg/kg, i.p.) and subtype-selective doses of the group II antagonist LY341495 (1 mg/kg, i.p.) did not significantly elevate serum corticosterone. Given the group I agonists results, it was surprising to find that group I selective and mGlu1 selective antagonists given alone also increased serum corticosterone. As with the agonists, the rise in serum corticosterone with LY393675 (an mGlu1/5 antagonist, EC50 = 20 nmol, i.c.v.) and LY367385 (an mGlu1 antagonist, 325 nmol, i.c.v.) were dose-dependent and consistent with their relative affinity for the group I mGlu receptors. The selective mGlu5 antagonist MPEP [2-methyl-6-(phenylethylnyl)pyridine] increased serum corticosterone but only at high doses (> 30 mg/kg, i.p.). A model involving the high glutamatergic tone on GABAergic interneurons in the paraventricular nucleus of the hypothalamus is discussed as a possible explanation for these results.

    Title A Fetal Lung Lesion Consisting of Bronchogenic Cyst, Bronchopulmonary Sequestration, and Congenital Cystic Adenomatoid Malformation: the Missing Link?
    Date August 2001
    Journal Fetal Diagnosis and Therapy
    Excerpt

    A fetus was found to have a large left thoracic cyst on routine prenatal ultrasound at 23 weeks of gestation. This lesion caused compression of the normal left lung tissue and contralateral mediastinal shift. At 23 weeks of gestation the cyst was percutaneously aspirated without subsequent reaccumulation of fluid. Serial ultrasounds showed decrease in the size of the cyst. The clinical diagnosis of congenital cystic adenomatoid malformation was made. At birth, the child had no respiratory distress, and a CT scan confirmed the finding of a fluid-filled cyst in the left chest. At the time of resection, a nonaerated extralobar bronchopulmonary sequestration (with a systemic arterial blood supply and separate pleural investment) was found. The dominant cyst had ciliated respiratory epithelium with cartilage, indicative of a bronchogenic cyst, and the remainder of the specimen had the histologic hallmarks of a congenital cystic adenomatoid malformation. The coexistence of three separate anomalies in one lesion suggests a common embryological link for these malformations.

    Title Diagnostic Accuracy of Intraoral Film and Direct Digital Images for Detection of Simulated Recurrent Decay.
    Date July 2001
    Journal Operative Dentistry
    Excerpt

    This study compared the diagnostic accuracy of bitewing images for detection of simulated recurrent caries using the following imaging modalities: Ektaspeed Plus film and different digital imaging system technologies comprised of a charge-coupled device (CCD) based digital imaging unit, a photo-stimulable phosphor (PSP) based unit and contrast- and brightness-enhanced PSP images. STUDY DESIGN: Twenty-four extracted posterior teeth with MOD inlay preparations were secured in models simulating a natural arrangement of teeth. Lesions were created in proximal boxes using dental burs of varying sizes. Defects were filled with wax and plaster and preparations were restored with composite or amalgam. RESULTS: Averages of receiver operating curve areas (Az) revealed diagnostic performances of Az = 0.74 for film, Az = 0.80 for CCD, Az = 0.73 for unenhanced PSP and Az = 0.64 for enhanced PSP. The differences between these means were significant (MANOVA p < 0.0001). Unenhanced PSP produced significantly poorer performance than other modalities. CCD performance was not significantly better than enhanced PSP. Lesions under radiopaque composite restorations were easier to detect, followed by those under amalgam and radiolucent composites across imaging modalities and lesion locations. Based on lesion location, those located at the buccal point angle were easiest to detect, followed by those at mid-gingival floor and lingual-point angle sites. CONCLUSIONS: Contrast and brightness-enhanced digital images enabled better signal detection and a comparable performance with film for detection of artificially induced recurrent caries.

    Title Temporally Explicit Habitat Ecology and the Coexistence of Species.
    Date June 2001
    Journal Proceedings. Biological Sciences / The Royal Society
    Excerpt

    Habitats may have dynamics that exist independently of the population densities of species occupying the habitat. For example, ephemeral habitat patches may disappear regardless of whether a particular species is present or not. Such habitat dynamics are frequently modelled by ignoring age-related variation in patch turnover rates. This can be thought of as a temporally implicit approach. An alternative, temporally explicit approach involves using age-structured models in order to describe variations in habitat dynamics. Simple models of coexistence between competing species show that temporally implicit models may be misleading where there is age-related variation in patch dynamics. Changing the shape of the patch survivorship function but not the average patch survivorship can result in mutual extinction, monocultures or coexistence of an inferior and a superior competitor. An explicit treatment of habitat demography may therefore offer improved predictive models and alternative landscape management strategies.

    Title New Method to Assess Scapular Upward Rotation in Subjects with Shoulder Pathology.
    Date April 2001
    Journal The Journal of Orthopaedic and Sports Physical Therapy
    Excerpt

    STUDY DESIGN: Test-retest repeated measures and correlational design. OBJECTIVES: To examine the reliability and validity of a "modified" digital inclinometer to assess scapular upward rotation during humeral elevation in the scapular plane BACKGROUND: Evidence exists that scapular motion is related to shoulder pathology; however, evaluation and treatment planning for shoulder rehabilitation often fails to include an objective assessment of scapular motion. METHODS AND MEASURES: Two-dimensional measurements by the inclinometer were taken with the arm in a static position. These data were compared to 3-dimensional measurements obtained using a magnetic tracking device with the arm fixed and during arm movement. Both methods were used to assess scapular upward rotation positions with the arm at rest and at 60 degrees , 90 degrees , and 120 degrees of humeral elevation in the scapular plane. Both scapulae were tested on a total of 39 subjects, 16 with shoulder pathology and 23 without. Reliability was assessed using repeated measurements from the inclinometer. Validity was assessed using 2 separate comparisons: inclinometer and magnetic tracking device under static arm conditions and inclinometer and magnetic tracking device during active arm elevation. Reliability and validity were assessed at all 4 arm positions. RESULTS: Intraclass correlation coefficients (ICC [3,1]) varied from 0.89 to 0.96. Pearson Product Moment correlation coefficients, used to assess validity of the static inclinometer, varied from r = 0.74 to 0.92 compared with the static magnetic tracking measures, and from r = 0.59 to 0.73 compared with the active magnetic tracking measures taken during arm elevation. CONCLUSIONS: The "modified" digital inclinometer demonstrated good to excellent intrarater reliability and good to excellent validity when measuring scapular upward rotation during static positions of humeral elevation in the scapular plane.

    Title Comparative Evaluation of Tuned Aperture Computed Tomography for the Detection of Mandibular Fractures.
    Date February 2001
    Journal Dento Maxillo Facial Radiology
    Excerpt

    OBJECTIVES: To compare the diagnostic efficacy of Tuned Aperture Computed Tomography (TACT) with conventional imaging modalities for detection of fractures of the mandible. METHODS: Fractures were induced using blunt trauma in human defleshed mandibles. Conventional extra-oral and indirect digital images, unprocessed TACT images reconstructed from eight and 16 basis images (BI) and iteratively restored TACT images from eight and 16 BI were used for fracture evaluation. Twelve observers recorded their diagnoses using a five-point confidence rating scale. The data were analysed using ROC curve analysis. RESULTS: Significant differences were found (P < 0.0001) in the areas under the curve (Az): film, 0.6954; digital images 0.6169; TACT unprocessed images using 8 BI, 0.7420; TACT unprocessed images using 8 BI, 0.7667; TACT unprocessed images using 16 BI, 0.7730; TACT iteratively restored images using 16 BI, 0.8143. No observer-based differences were found. Fractures in the condylar and coronoid regions were more difficult to detect than those in the ramus and body of the mandible. CONCLUSIONS: Iteratively restored TACT images generated using 16 BI had a superior diagnostic performance to all the other imaging modalities. Studies are in order to evaluate its in vivo potential.

    Title Anti-dna Antibodies Cross-reacting with Laminin Inhibit Trophoblast Attachment and Migration: Implications for Recurrent Pregnancy Loss in Sle Patients.
    Date February 2001
    Journal American Journal of Reproductive Immunology (new York, N.y. : 1989)
    Excerpt

    PROBLEM: Systemic lupus erythematosus (SLE), an autoimmune disease, is associated with reduced fetal survival, recurrent abortions, and other pregnancy complications. Some of the autoantibodies found in SLE bind to laminins (LNs), which play an important role in the implantation of the fertilized ovum in humans. METHOD OF STUDY: To elucidate the role of these specific autoantibodies, chorionic villous explants from 6 7-week-old human placentas were established as organ cultures on laminin-1 (LN-1), collagen IV (CN-IV) or uncoated culture dishes. The cultures were then exposed to a mouse monoclonal anti-DNA/anti-LN-1 antibody, to human polyclonal lupus antibodies cross-reacting with LN-1, a function-blocking polyclonal antibody to LN-1, polyclonal antibodies to CN-IV, or IgG control. RESULTS: The explants attached to LN-1 and CN-IV, but not to uncoated culture dishes. LN-1 promoted migration of trophoblast, whereas CN-IV promoted migration of fibroblast-like cells. Trophoblast attachment and migration were abolished in a dose-dependent manner by all three antibodies to LN-1, but not by antibodies to CN-IV or IgG control. Furthermore, the effect of anti-LN antibodies was abolished by preincubating them with LN-1. CONCLUSIONS: These studies suggest that anti-DNA antibodies cross-reacting with LNs may play a role in early pregnancy failure in SLE patients by interfering with placental implantation.

    Title Fetal Obstructive Uropathy in Trisomy Syndromes.
    Date January 2001
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Fetal obstructive uropathy has seldom been described in trisomy syndromes, and its relationship to these syndromes remains unclear. Five trisomic male fetuses, four with trisomy 18 and one with trisomy 21, were identified out of 110 fetuses evaluated for fetal obstructive uropathy. We performed detailed examination on the urinary tracts of four of these fetuses, three with trisomy 18 and one with trisomy 21, following termination in the second trimester. All four had a markedly distended urinary bladder (megacystis), abdominal wall distension, and a small, poorly developed urethra thoughout its full length. All four also had poor development of the prostate with virtual absence of glandular development, as compared to age-matched controls. Posterior urethral valves were not identified in any case. Three of the fetuses (two with trisomy 18 and one with trisomy 21) had unilateral or bilateral hydroureters, and resulting renal tubulocystic or glomerulocystic change. Review of this database reveals an unexpectedly high frequency of trisomies, particularly trisomy 18, suggesting that the relationship may not be coincidental. Abnormal prostate development may be causally related to fetal obstructive uropathies and may be an under-recognized trait in trisomy syndromes. Karyotypic analysis of all fetuses with obstructive uropathy is important since in utero surgical intervention may be contraindicated in cases of fetal aneuploidy.

    Title Treatment of Severe Congenital Diaphragmatic Hernia by Fetal Tracheal Occlusion: Clinical Experience with Fifteen Cases.
    Date December 2000
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Our purpose was to determine whether prenatal tracheal occlusion improves survival in a selected population of fetuses affected by severe congenital diaphragmatic hernia. STUDY DESIGN: Fetuses with isolated congenital diaphragmatic hernia were selected as candidates for fetal intervention by specific criteria designed to predict a 90% mortality rate with conventional postnatal treatment. RESULTS: Fifteen fetuses underwent tracheal occlusion with 5 survivors (33%). Two fetuses were lost to early preterm labor. In 13 mothers, postoperative gestation ranged from 19 to 68 days, with a mean duration of pregnancy after tracheal occlusion of 38 days. The 5 survivors were hospitalized for an average of 76 days. Despite dramatic lung growth in some fetuses after tracheal occlusion, intensive management was required, and most deaths were caused by respiratory insufficiency. CONCLUSION: Prenatal tracheal occlusion can result in impressive lung growth in a subset of fetuses with severe congenital diaphragmatic hernia. However, survival remains compromised by pulmonary functional abnormality and the consequences of prematurity.

    Title Assessment of Fetal Lung Volumes and Liver Herniation with Magnetic Resonance Imaging in Congenital Diaphragmatic Hernia.
    Date December 2000
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: We evaluated the use of fetal magnetic resonance imaging in predicting outcomes after ultrasonographic diagnosis of left-sided congenital diaphragmatic hernia. STUDY DESIGN: Forty-one pregnant women carrying fetuses with congenital diaphragmatic hernia underwent 43 magnetic resonance imaging scans. Lung volumes were calculated by summing the areas on 6-mm axial sections. The presence or absence of liver herniation was noted. A liver/diaphragm ratio was obtained by using the distances from the superior aspect of the liver and the diaphragmatic remnant to the apex of the chest. RESULTS: Mean gestational age was 26 weeks and overall survival was 59%. Neither right, left, nor total lung volume measurements were predictive of survival. Liver herniation into the left side of the chest was predictive of outcome at P<.05. The liver/diaphragm ratio was predictive of outcome at P = .03. CONCLUSION: Fetal magnetic resonance imaging permits calculation of lung volumes, but these volumes are not predictive of outcome. However, both the presence of liver herniation and the volume of liver within the chest, as reflected by the liver/diaphragm ratio, help predict outcome in left-sided congenital diaphragmatic hernia.

    Title Blockade of Pilocarpine-induced Cerebellar Phosphoinositide Hydrolysis with Metabotropic Glutamate Antagonists: Evidence for an Indirect Control of Granule Cell Glutamate Release by Muscarinic Agonists.
    Date August 2000
    Journal Neuroscience Letters
    Excerpt

    The ability in vivo of the muscarinic agonist, pilocarpine, to increase phosphoinositol (PI) hydrolysis in lithium pretreated rats was investigated by measuring the accumulation of [(3)H]inositol phosphates (IP). As expected, 20 mg/kg s.c. pilocarpine, a muscarinic agonist, increased PI hydrolysis in the striatum, frontal cortex and hippocampus. Somewhat surprisingly, an increase in IP was also found in the cerebellar homogenates. In all four tissues the pilocarpine-induced effect could be completely inhibited by pretreatment with the muscarinic antagonist scopolamine (1.2 mg/kg i. p.). It was also found that the cerebellar but not the hippocampal pilocarpine-induced rise in PI hydrolysis could be blocked by the metabotropic glutamate (mGlu) receptor antagonist, LY341495 (100 nmol, i.c.v.). The same dose of LY341495 was found to also block both the cerebellar and hippocampal increase in IP formed by stimulation with the group I mGlu receptor agonist 3, 5-dihydroxyphenylglycine (1 micromol, i.c.v.). Given this data and the current information on the distribution of muscarinic and mGlu receptors in the cerebellum, it is suggested that these results may be a reflection of pilocarpine acting at M(2) receptors to indirectly increase glutamate release from parallel fibers by inhibition of gamma-aminobutyric acid-releasing Golgi cells.

    Title Percutaneous Fixation of Proximal Humeral Fractures.
    Date June 2000
    Journal Clinical Orthopaedics and Related Research
    Excerpt

    The purpose of the current study is to evaluate the technique of closed reduction and percutaneous pinning of proximal humeral fractures and to determine whether this technique provides enough stability to permit early active range of motion and subsequent fracture healing. Fractures were classified according to Neer et al and were included if the surgical or anatomic neck were angulated greater than 45 degrees, separation between fragments was greater than 1 cm, or the greater tuberosity was displaced more than 0.5 cm. There were 21 Type II, 16 Type III, and four Type IV fractures. Fractures were pinned using distally threaded Dynamic Hip Screw guide pins, 2-mm Kirschner wires, or 2.5-mm distally threaded Schantz pins. Patients were evaluated for union rates and motion. Assessment was made using the Modified American Shoulder and Elbow Surgeons Form. Thirty-six patients with 37 fractures were available for review with followup averaging 40 months (range, 12-68 months). All patients with Neer Type IV fractures did not respond to fixation and three had avascular necrosis develop, irrespective of the type of pin used. In the remaining 33 patients with Neer Type II and Type III fractures, a union rate of 94% was observed at an average of 2.6 months. All patients had good functional results. In the current series, there were no failures using Schantz pins. There was a 20% failure rate with Dynamic Hip Screw pins (2% if the patients with Type IV fractures were excluded) and a 100% failure rate with Kirschner wires. Stable fixation with early motion and subsequently good results can be obtained using percutaneous fixation in patients with Type II and Type III fractures; however, terminally threaded pins must be used and smooth Kirschner wires must be avoided. Percutaneous fixation cannot be recommended in patients with Type IV fractures.

    Title Coexpression of Full-length Gamma-aminobutyric Acid(b) (gaba(b)) Receptors with Truncated Receptors and Metabotropic Glutamate Receptor 4 Supports the Gaba(b) Heterodimer As the Functional Receptor.
    Date June 2000
    Journal The Journal of Pharmacology and Experimental Therapeutics
    Excerpt

    Direct evidence is lacking to show whether the gamma-aminobutyric acid (GABA)(B) gb1-gb2 heterodimer is the signaling form of the receptor. In this study, we tested whether gb1a or gb2 subunits when coexpressed with truncated receptors or metabotropic glutamate receptor mGluR4 could form functional GABA receptors. Coexpression of the ligand binding N-terminal domain of gb1a or the C-terminal portion of gb1a composing the seven-transmembrane segments and intracellular loops with gb2 could not reconstitute functional receptors. We next examined whether mGluR4, which forms homodimers and is structurally related to GABA(B), could act as a surrogate coreceptor for gb1 or gb2. The coexpression of mGluR4 and gb1a led to the expression of gb1a monomers on cell surface membranes as determined by immunoblot analysis and flow cytometry. However, mGluR4-gb1a heterodimers were not formed, and membrane-expressed gb1a monomers were not functionally coupled to adenylyl cyclase in human embryonic kidney 293 cells or activated inwardly rectifying potassium (Kir) channels in Xenopus oocytes. Similarly, the coexpression of mGluR4 and gb2 led to nonfunctional GABA receptors. GABA-activated distal signaling events resulted only after the coexpression and heterodimerization of gb1 and gb2. Taken together with the truncated receptor studies, the data suggest that a high degree of structural specificity is required to form the functional GABA(B) receptor that is a gb1-gb2 heterodimer.

    Title Molecular and Fetal Tissue Biopsy Capabilities Are Needed to Maximize Prenatal Diagnosis of Junctional Epidermolysis Bullosa: Fetal Skin Biopsy Using a 1-mm Microendoscope.
    Date May 2000
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To describe a minimally invasive micro-endoscopic technique for fetal skin biopsy and direct examination for a lethal skin condition. MATERIALS AND METHODS: Direct fetoscopic examination of a fetus was undertaken along with full thickness skin biopsies at 19 weeks' gestation. RESULTS: No phenotypic expressions of the lethal condition were visualized and six full thickness skin biopsies were collected. Pathological examination revealed normal skin structures not consistent with junctional epidermolysis bullosa (JEB). CONCLUSION: Minimally invasive examination with the 1 mm endoscope allows direct fetal phenotypic evaluation, full thickness skin biopsies, with risks similar to amniocentesis.

    Title Fetal Therapy for Obstructive Uropathy: Past, Present.future?
    Date April 2000
    Journal Pediatric Nephrology (berlin, Germany)
    Excerpt

    Antenatal treatment of obstructive uropathy, although widely performed, remains controversial. An overview of prenatal therapy for obstructive uropathy, the limitations of the early published experience, advances of recent years, and future directions for treatment are reviewed. The clinical approach and outcomes of the Fetal Treatment Program of Hutzel Hospital and Wayne State University are presented. Patient selection for antenatal treatment is based on the existence of a significant threat of neonatal death due to pulmonary hypoplasia, pending exclusion criteria such as anatomical structural anomalies and chromosomal defects. Ultrasonography, karyotyping, and sequential urinary electrolyte analysis are essential. Current treatment involves the placement under ultrasonic guidance of a Rodeck vesicoamniotic shunt. Recent technical advances include the use of amnioinfusion for fetal visualization, temporary fetal paralysis, routine antibiotics, and more-precise catheter placement. The establishment of standardized short- and long-term outcome measures and the documentation of fetal and maternal complications are in progress. Procedural refinement, development of fetoscopic techniques and equipment, identification of urinary markers to aid patient selection, and the collection of multicenter outcome data will assist the future management of prenatally detected obstructive uropathy.

    Title Treatment of Heterotopic Cervical and Intrauterine Pregnancy.
    Date April 2000
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To find a suitable technique to selectively terminate a cervically implanted embryo while maintaining viability of a concomitant intrauterine pregnancy. METHODS: A 34-year-old patient achieved a twin pregnancy after 4 IVF attempts. Ultrasound revealed a viable intrauterine and cervical pregnancy. Given our experience with KCl injection for fetal reduction, we offered the patient an attempt to reduce the cervical pregnancy. RESULTS: Best visualization in this case was obtained by transabdominal scanning. A 6-inch 20-gauge spinal needle was inserted transcervically and maneuvered into the thorax of the embryo. Fetal heart rate ceased even before KCl could be injected. Then 3 cm(3) of saline were injected to provide better visualization of the cervical fetus, and to confirm absence of heart beat. The patient had minor vaginal bleeding for several days. The intrauterine pregnancy progressed uneventfully through 36(1)/(2) weeks with delivery of a healthy, 2, 700-gram newborn. CONCLUSION: Cervical pregnancy is usually considered a life-threatening event. Other factors such as concomitant intrauterine pregnancy and the patient's infertility history generally would be secondary concerns. In this case, we were able to selectively terminate the cervical pregnancy, while preserving the intrauterine one, allowing this couple to have a healthy newborn. Further cases will be necessary to appropriately define risk rates for such an approach.

    Title Severe Oligohydramnios with Intact Membranes: an Indication for Diagnostic Amnioinfusion.
    Date April 2000
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To quantify the improvement in ultrasonographic fetal imaging following diagnostic amnioinfusion for the indication of unexplained midtrimester oligohydramnios. METHODS: Patients referred for unexplained midtrimester oligohydramnios were retrospectively reviewed. Videotapes of those undergoing diagnostic antenatal amnioinfusion were analyzed for quality of visualization of routinely imaged structures before and after the infusion procedure. RESULTS: The overall rate of adequate visualization of fetal structures improved from 50.98 to 76.79% (p < 0.0001). In fetuses having preinfusion-identified obstructive uropathy, there was improvement in identification of associated anomalies from 11.8 to 31.3%. CONCLUSIONS: Several authors have suggested that diagnostic amnioinfusion can facilitate fetal imaging and increase diagnostic precision in the setting of unexplained severe oligohydramnios. We have quantified the improvement in the rate of optimal visualization of fetal structures which likely translates, in experienced hands, into this observed improved diagnostic precision. Of particular importance is the improvement in appreciation of associated anomalies in cases of obstructive uropathy in which such findings may determine whether or not invasive fetal therapy is indicated.

    Title Ultrasound Screening for Fetal Chromosome Anomalies.
    Date March 2000
    Journal American Journal of Medical Genetics
    Excerpt

    Ultrasound evidence for aneuploidy may be found in almost every organ of the fetus and can be used to modify the risk of aneuploidy. The diagnosis of these minor anomalies on second-trimester ultrasonography will increase the risk of an abnormal karyotype whereas the absence of these findings may reduce this danger. The most specific and most ominous isolated markers for fetal aneuploidy are nuchal findings (edema or cysts), indicating the need to obtain a fetal karyotype in all cases irrespective of maternal age or results of biochemical serum screening. Hyperechoic fetal bowel is apparently also a strong indicator of fetal aneuploidy. Other isolated sonographic markers may increase the risk of an abnormal karyotype three- to ninefold. Most sonographic markers for aneuploidy specify an increased risk for Down syndrome, but choroid plexus cysts are apparently more specific for trisomy 18. Along with other screening methods, ultrasound screening for fetal aneuploidy should be used routinely to identify additional pregnancies at need for evaluation of fetal karyotype.

    Title Routine Prenatal Diagnosis of Aneuploidy by Fish Studies in High-risk Pregnancies.
    Date February 2000
    Journal American Journal of Medical Genetics
    Excerpt

    This study is a prospective clinical trial with fluorescent in situ hybridization (FISH) as a "routine" test for prenatal detection of the most common aneuploidies in high-risk pregnancies. Since April 1996, FISH studies with multicolor, commercially available, specific probes for chromosomes 13, 18, 21, X, and Y have been routinely performed in our cytogenetic laboratory on uncultured chorionic villous samplings (CVS), amniotic fluid samples, or fetal blood obtained by cordocentesis from patients with major or minor fetal anomalies detected by ultrasonography. Among the 4,193 prenatal samples analyzed between April 1996 and June 1998, routine FISH studies were ordered by the referring physicians on 301 (7.2%) cases. Aneuploidies were detected in 32 (10.6%) samples. Fourteen trisomy-21, 10 trisomy-18, 3 trisomy-13, 4 monosomies of X, and 1 case of triploidy were diagnosed by FISH. All 1,505 hybridizations were informative, and all 301 results were available and reported to the referring physicians in 24-48 hr. All relevant FISH results were confirmed by subsequent cytogenetic analysis. In 10 (3.8%) cases with normal FISH results, the final cytogenetic analysis revealed abnormal chromosomal rearrangements that could not be detected by the routine FISH studies. We conclude that rapid FISH analysis of interphase, uncultured fetal cells is an accurate and very sensitive method for routine prenatal diagnosis of the most common aneuploidies in high-risk pregnancies.

    Title Open Fetal Surgery for Life-threatening Fetal Malformations.
    Date January 2000
    Journal Seminars in Perinatology
    Excerpt

    After more than two decades of experimental and clinical work, fetal surgery has become an accepted treatment modality for selected fetuses with life-threatening anomalies. Color Doppler ultrasound and ultrafast fetal magnetic resonance imaging have enhanced the accuracy of prenatal evaluation traditionally made by ultrasound alone. Fetal lung masses associated with hydrops are nearly 100% fatal. These lesions can be resected in utero if they are predominantly solid or multicystic. Thoracoamniotic shunting may be effective in the setting of a single large predominant cyst. Fetuses diagnosed with left congenital diaphragmatic hernia before 26 weeks' gestation with liver herniation and a sonographic right lung to head circumference ratio (LHR) of less than one may benefit from fetal tracheal occlusion. Fetal sacrococcygeal teratoma complicated with placentomegaly, hydrops, or progressive high output heart failure may benefit from in utero resection of the tumor. Although preterm labor still remains the Achilles heel of open fetal surgery, effective tocolysis may, in the future, expand the scope of fetal surgery.

    Title Fetal Interventions for Obstructive Uropathy.
    Date January 2000
    Journal Seminars in Perinatology
    Excerpt

    Obstructive uropathy is a significant source of morbidity and mortality in the neonate and infant, despite advances in postnatal management. Diagnosis is typically made early in the second trimester on the basis of sonographic measurements. In utero therapy holds promise for improved outcomes by preventing progressive urinary tract damage and permitting drainage of urine into the amniotic space to minimize the pulmonary sequelae of oligohydramnios. Multiple studies with animal models have showed the benefits of midgestational intervention, but large prospective, randomized studies have not yet been performed to confirm these findings in humans. Standardization of the diagnostic evaluation allows for refined patient selection, resulting in improved postnatal outcomes after fetal vesicoamniotic shunting. Research into the role of specific growth factors and immunoproteins in renal development and function may further improve patient selection and outcome. This article reviews diagnosis, technique, and outcomes for fetal treatment of obstructive uropathy.

    Title Ontogeny of Isolated Ultrasound Markers for Fetal Aneuploidy.
    Date December 1999
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To evaluate the natural history of isolated ultrasound markers for fetal aneuploidy observed at 14-16 weeks of affected gestations. STUDY DESIGN: 76 aneuploid gestations were diagnosed among a predominantly low-risk population undergoing targeted ultrasonography in the early second trimester. Indications for evaluation of fetal karyotype included fetal malformations or sonographic markers for aneuploidy, maternal age over 35 years and abnormal serum screening results. Markers were re-evaluated at the time of amniocentesis or at pregnancy termination for fetal anomalies. RESULTS: Sonographic markers for aneuploidy (SMA) were observed in 68 of 76 aneuploid gestations diagnosed in the study group. In 46 cases, SMA were associated with major fetal malformations and in 22 cases, markers were isolated. Only 2 of 22 isolated markers for aneuploidy were documented at the time of amniocentesis. CONCLUSION: Isolated ultrasound markers for aneuploidy are transient and may disappear later on in gestation. Transvaginal sonography at 14-16 weeks of gestation appears to provide the best time window for detection of markers for fetal abnormal karyotype.

    Title Improvement in Hindbrain Herniation Demonstrated by Serial Fetal Magnetic Resonance Imaging Following Fetal Surgery for Myelomeningocele.
    Date December 1999
    Journal Jama : the Journal of the American Medical Association
    Excerpt

    CONTEXT: Hindbrain herniation occurs in a large percentage of children with myelomeningocele and is the leading cause of death in this population. The effect of early fetal closure of myelomeningocele on hindbrain herniation is unknown. OBJECTIVE: To determine whether early fetal closure of myelomeningocele affects hindbrain herniation. DESIGN: Case series of patients undergoing fetal myelomeningocele closure with serial measurements of hindbrain herniation and a mean follow-up of 182 days. SETTING: Tertiary care medical center. PARTICIPANTS: Ten patients undergoing fetal myelomeningocele closure at 22 to 25 weeks' gestation between March 1998 and February 1999. MAIN OUTCOME MEASURES: Need for shunt placement; degree of hindbrain herniation (grades 0-3) found on magnetic resonance imaging (MRI) performed prior to surgery and 3 and 6 weeks after fetal surgery, as well as shortly after birth; gestational age at delivery. RESULTS: All initial fetal MRI scans performed at 19 to 24 weeks' gestation showed significant (grade 3) cerebellar herniation and absence of spinal fluid spaces around the cerebellum. Six fetuses were delivered electively at 36 weeks' gestation after lung maturity was established. The other 4 were delivered prematurely, at 25, 30, 30, and 31 weeks of gestation, and the 25-week gestation neonate died. All 9 surviving neonates showed improvement in the hindbrain hernia at the 3-week postoperative fetal scan (grade 2, n = 4; grade 1, n = 5). On the postnatal scan, all patients showed grade 1 hindbrain herniation. Only 1 patient required placement of a ventriculoperitoneal shunt. CONCLUSION: In this series of patients, fetal myelomeningocele closure resulted in improvement in hindbrain herniation as demonstrated by serial MRI scans.

    Title Selective Termination for Structural, Chromosomal, and Mendelian Anomalies: International Experience.
    Date November 1999
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Our purpose was to evaluate the outcomes of selective termination for fetal anomalies at 8 centers with the largest known experiences worldwide. STUDY DESIGN: Outcomes in 402 cases of selective termination in pregnancies with dizygotic twins from 8 centers in 4 countries were analyzed by year, gestational age at procedure, and indication. Reductions of fetuses were as follows: 2 to 1, n = 345; 3 to 2, 39; >/=4 to 2 or 3, n = 18. Potassium chloride was used in all procedures. RESULTS: Selective termination resulted in delivery of a viable infant or infants in >90% of cases. Loss up to 24 weeks occurred in 7.1% of cases in which the final result was a singleton fetus and in 13.0% of cases in which the final result was twins. Loss was 6.6% as a result of structural abnormalities, 7.0% for chromosomal abnormalities, and 10% for mendelian abnormalities (difference not statistically significant). Loss rates for procedures were as follows: 9-12 weeks, 5.4%; 13-18 weeks, 8.7%; 19-24 weeks, 6.8%; and >/=25 weeks, 9.1% (difference not statistically significant). Mean gestational age at delivery was 35.7 weeks. No differences were seen in outcomes by maternal age. The rate of very early premature deliveries has fallen in recent years. There were no known cases of disseminated intravascular coagulation or serious maternal complications. CONCLUSION: (1) Selective termination, in the most experienced hands, can be technically performed in all 3 trimesters with good outcomes in >90% of cases. (2) The previously observed increase in second- versus first-trimester losses has diminished. (3) Third-trimester procedures, where legal, can be performed with a good outcome for the surviving fetus.

    Title Second-trimester Maternal Serum Marker Screening: Maternal Serum Alpha-fetoprotein, Beta-human Chorionic Gonadotropin, Estriol, and Their Various Combinations As Predictors of Pregnancy Outcome.
    Date November 1999
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: We evaluated the value of all 3 common biochemical serum markers, maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, and unconjugated estriol, and combinations thereof as predictors of pregnancy outcome. STUDY DESIGN: A total of 60,040 patients underwent maternal serum screening. All patients had maternal serum alpha-fetoprotein measurements; beta-human chorionic gonadotropin was measured in 45,565 patients, and 24,504 patients had determination of all 3 markers, including unconjugated estriol. The incidences of various pregnancy outcomes were evaluated according to the serum marker levels by using clinically applied cutoff points. RESULTS: In confirmation of previous observations, increased maternal serum alpha-fetoprotein levels (>2.5 multiples of the median) were found to be significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, intrauterine growth restriction, intrauterine fetal death, oligohydramnios, and abruptio placentae. Increased beta-human chorionic gonadotropin levels (>2.5 multiples of the median [MoM]) were significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, and intrauterine fetal death. Finally, decreased unconjugated estriol levels (<0.5 MoM) were found to be significantly associated with pregnancy-induced hypertension, miscarriage, intrauterine growth restriction, and intrauterine fetal death. As with increased second-trimester maternal serum alpha-fetoprotein levels, increased serum beta-human chorionic gonadotropin and low unconjugated estriol levels are significantly associated with adverse pregnancy outcomes. These are most likely attributed to placental dysfunction. CONCLUSION: Multiple-marker screening can be used not only for the detection of fetal anomalies and aneu-ploidy but also for detection of high-risk pregnancies.

    Title Analysis and Characterization of Hematopoietic Progenitor Cells from Fetal Bone Marrow, Adult Bone Marrow, Peripheral Blood, and Cord Blood.
    Date September 1999
    Journal Pediatric Research
    Excerpt

    Hematopoietic stem cell transplantation has been increasingly used to replace a defective hematopoietic system and to treat various genetic defects as well as malignant diseases. However, the limitations of conventional bone marrow transplantation have stimulated an intense interest in exploring the use of alternative sources of hematopoietic stem cells, including peripheral blood mononuclear cells (PBMC) and cord blood (CB). A major investigative effort of our laboratory has been focused on evaluating fetal bone marrow (FBM) for transplantation. The current study compares and characterizes the functional and phenotypic characteristics of FBM, CB, adult bone marrow (ABM), and PBMC by clonogenicity assays, immunogenicity, and the quantification of progenitor cells. There was a striking difference in the proportion of CD34+ cells in FBM, ABM, PBMC, and CB (24.6%, 2.1%, 0.5%, and 2.0%, respectively). The clonogenic potential, as measured by colony forming unit in culture (CFU-C) assay, was significantly higher in FBM when compared with ABM, PBMC, and CB (202.5, 73.5, 40.8, and 65.5 colonies/10(5) cells, respectively). There was a significant decrease in proliferative responsiveness in mixed lymphocyte reaction (MLR) assay of FBM and CB compared with ABM and PBMC. These observations indicate that each source of hematopoietic stem cells has different intrinsic properties closely correlated with ontogenetic age that is a vital determinant for phenotypic characteristics, lineage commitments, immunogenicity, and proliferative potentials.

    Title Ontogeny of Recurrent Hydrocephalus: Presentation in Three Fetuses in One Consanguineous Family.
    Date September 1999
    Journal Fetal Diagnosis and Therapy
    Excerpt

    A consanguineous couple had 3 pregnancies in which prenatally diagnosed hydrocephalus was observed (in 1 female and 2 male fetuses). This case appears to represent an autosomal recessive form of hydrocephalus, given the consanguinity, affected sibs of both genders, and no evidence for intrauterine infection, chromosome abnormality, or neural tube defect.

    Title Amnioinfusion in the Evaluation of Fetal Obstructive Uropathy: the Effect of Antibiotic Prophylaxis on Complication Rates.
    Date August 1999
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: Amnioinfusion plays an important role in the intrauterine evaluation and treatment of fetal obstructive uropathy. However, it may significantly increase the risk for chorioamnionitis, premature rupture of membranes and premature labor. We evaluated the impact of prophylactic antibiotics on postamnioinfusion complications. METHODS: Thirty pregnancies complicated by fetal obstructive uropathy, treated by amnioinfusion and with documentation of pregnancy outcome were identified from our database. Pregnancy outcomes were compared between patients who were treated with prophylactic antibiotics and those with no prophylaxis. RESULTS: Chorioamnionitis was diagnosed in 3 out of 15 (20%) patients who did not receive prophylactic antibiotics as compared to 2 (13%) in the treated group. The overall rate of serious obstetrical complication was significantly higher in the untreated group (66 vs. 20%; p = 0. 021). Patients receiving prophylactic antibiotics delivered at a significantly greater gestational age than those who did not receive antibiotics (34.0 +/- 3.7 vs. 31.3 +/- 1.9 weeks, respectively; p = 0.018). CONCLUSIONS: Our study supports the use of oral prophylactic antibiotics as being effective in reducing the previously observed significant risks associated with amnioinfusion in fetal obstructive uropathy.

    Title Differential Effect of Advanced Maternal Age on Prenatal Diagnosis of Trisomies 13, 18 and 21.
    Date August 1999
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Nondisjunction associated with advanced maternal age, a well-established factor in the etiology of autosomal trisomy, should equally affect all chromosomes. In this study we evaluate the association of advanced maternal age with the occurrence of potentially viable autosomal trisomies (13, 18 and 21). 275 aneuploid pregnancies were ascertained prenatally and were grouped according to chromosome anomaly diagnosed. Mean maternal age was significantly younger (p = 0.009) in pregnancies affected by trisomy 13 than in pregnancies with trisomy 21. An intermediate mean maternal age was observed in pregnancies affected by trisomy 18. Our study shows a trend of the more severe, but potentially viable, autosomal trisomies to be diagnosed at younger maternal age. This may substantiate the 'relaxed selection hypothesis' proposed to explain the association of aneuploid conceptions with advanced maternal age.

    Title Distribution of Neural Tube Defects As a Function of Maternal Weight: No Apparent Correlation.
    Date August 1999
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVES: Maternal nutritional deficiency is an important predisposing factor to congenital neural tube defects (NTDs). It was hypothesized that obese women may have an increased risk for NTDs. The aim of the present study was to address this question in a large cohort. METHODS: A total of 72,915 consecutive cases of biochemical screening that had documented maternal weights and pregnancy outcomes were identified from the Quest Diagnostic Laboratories database. Patients were divided into five ranges of maternal weights, and the incidence of NTDs was calculated for each group. Based on the different definitions of maternal overweight, the data were also analyzed based on 2 groups only, obese and nonobese, using three cutoff points. RESULTS: Seventy-nine pregnancies were complicated by NTDs (incidence of 1.08 per 1,000 pregnancies). Differences between maternal weights ranges were not found to be statistically significant (chi2 = 5.997, p = 0.19, power = 0.99). Differences between obese and nonobese mothers were not found to be statistically significant for all three analyses as well. CONCLUSIONS: Our present results do not support an association between maternal obesity and NTDs.

    Title Long-term Outcome in Children After Antenatal Intervention for Obstructive Uropathies.
    Date August 1999
    Journal Lancet
    Excerpt

    BACKGROUND: Antenatal intervention has been done for fetal obstructive uropathy for over a decade, yet little is known about long-term outcomes. To assess the long-term implications of fetal intervention, we reviewed the outcomes of children who underwent vesicoamniotic shunt placement. METHODS: We reviewed the clinical outcomes of 14 children who underwent vesicoamniotic shunt placement at our institution and who survived beyond 2 years of age. FINDINGS: In 1987-96, 34 patients underwent vesicoamniotic shunt placement. 13 died and 21 survived, of whom 17 are now more than 2 years old. Three survivors were lost to follow-up. Mean age at follow-up was 54.3 months (range 25-114). Final diagnoses included prune belly syndrome (seven cases), posterior urethral valves (four), urethral atresia (one), vesicoureteral reflux (one), and megacystis (one). Height was below the 25th percentile in 12 (86%) with seven (50%) below the 5th percentile. Five (36%) had renal failure and had successful transplantation, three (21%) have renal insufficiency, and six (43%) have normal renal function. Seven (50%) are acceptably continent, five (36%) have not yet begun toilet-training, and two (14%) are incontinent. Three of four children with valves needed bladder augmentation. INTERPRETATION: Antenatal intervention may help those fetuses with the most severe forms of obstructive uropathy, usually associated with a fatal neonatal course. Intervention achieves outcomes similar to less severe cases that are usually diagnosed postnatally.

    Title International, Collaborative Assessment of 146,000 Prenatal Karyotypes: Expected Limitations if Only Chromosome-specific Probes and Fluorescent In-situ Hybridization Are Used.
    Date July 1999
    Journal Human Reproduction (oxford, England)
    Excerpt

    The development of chromosome-specific probes (CSP) and fluorescent in-situ hybridization (FISH) has allowed for very rapid identification of selected numerical abnormalities. We attempt here to determine, in principle, what percentage of abnormalities would be detectable if only CSP-FISH were performed without karyotype for prenatal diagnosis. A total of 146 128 consecutive karyotypes for prenatal diagnosis from eight centres in four countries for 5 years were compared with predicted detection if probes for chromosomes 13, 18, 21, X and Y were used, and assuming 100% detection efficiency. A total of 4163 abnormalities (2.85%) were found including 2889 (69. 4%) (trisomy 21, trisomy 18, trisomy 13, numerical sex chromosome abnormalities, and triploidies) which were considered detectable by FISH. Of these, 1274 were mosaics, translocations, deletions, inversions, rings, and markers which would not be considered detectable. CSP-FISH is a useful adjunct to karyotype for high risk situations, and may be appropriate in low risk screening, but should not be seen as a replacement for karyotype as too many structural chromosome abnormalities will be missed.

    Title Fetal Uropathy.
    Date June 1999
    Journal Current Opinion in Obstetrics & Gynecology
    Excerpt

    Our understanding of the causes, mechanisms, and prenatal management of fetal obstructive uropathy has increased significantly. Improved methods of prenatal evaluation have allowed the better selection of fetuses for invasive therapy, and studies indicate better survival and renal outcomes in carefully selected cases. New biological markers in fetal urine may provide a better understanding of the pathological processes of renal damage, additional prognostic markers, and lead to non-surgical approaches to preventing renal damage.

    Title Multifetal Pregnancy Reductions of Triplets to Twins: Comparison with Nonreduced Triplets and Twins.
    Date June 1999
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Multifetal pregnancy reduction has been shown to improve survival rates in high-order multifetal pregnancies (>/=4). There is, however, some controversy as to whether multifetal pregnancy reduction improves pregnancy outcomes of triplets reduced to twins. The purpose of this study was to evaluate this issue by comparing outcomes of triplet gestations undergoing reduction to twins with outcomes of nonreduced twin gestations and expectantly managed triplet gestations. STUDY DESIGN: The study included 143 triplet pregnancies that underwent reduction to twins over a 10-year period at a single center. These were compared with 12 nonreduced triplet pregnancies from the Wayne State University Perinatal Database and with 2 groups of twin pregnancies: 605 from the Wayne State University Perinatal Database and 207 from the Quest Diagnostics Database. RESULTS: The miscarriage rate for expectantly managed triplets was 25%, compared with 6.2% for triplets reduced to twins. This rate was similar to the rates for both groups of nonreduced twins: 5.8% (Quest) and 6.3% (Wayne State University). Severe prematurity occurred in 25% of nonreduced triplets compared with 4. 9% of twins after reduction. This rate was also similar to that of nonreduced twins: 7.7% (Quest) and 8.4% (Wayne State University). The mean gestational age at delivery for expectantly managed triplets (32.9 +/- 4.7 weeks) was significantly shorter than for triplets reduced to twins (35.6 +/- 3.1 weeks). By comparison, nonreduced twins had a mean gestational age at delivery of 35.8 +/- 3.9 weeks for Quest and 34.4 +/- 3.6 weeks for Wayne State University. Mean birth weights were significantly lower in expectantly managed triplets as compared with triplets undergoing reduction to twins (1636 +/- 645 g vs 2381 +/- 602 g, respectively). Nonreduced twins had a mean birth weight of 2254 +/- 653 g for Quest and 2123 +/- 634 g for Wayne State University. Pregnancy loss rates, mean length of gestation, and mean birth weight did not vary significantly between triplets who underwent reduction to twins and nonreduced twins. CONCLUSIONS: Reduction of triplets to twins significantly reduces the risk for prematurity and low birth weight and may also be associated with a reduction in overall pregnancy loss. This suggests that multifetal pregnancy reduction of triplets to twins is a medically justifiable procedure not only from an actuarial viewpoint but also from the ethical perspective of supporting patients' autonomy and respect for patients' individual circumstances.

    Title Determinants of Parental Decisions After the Prenatal Diagnosis of Down Syndrome.
    Date June 1999
    Journal American Journal of Medical Genetics
    Excerpt

    We evaluated demographic factors and factors specific to the current pregnancy, and their relationship to the decision to continue or terminate a pregnancy after prenatal diagnosis of Down syndrome. All cases of Down syndrome (DS) managed at a tertiary care center from 1989-1997 were retrospectively analyzed with respect to maternal age, parity, gestational age, sonographic findings, insurance status, and race. Of 145 cases of trisomy 21, 19 (13.1%) of women chose continuation of pregnancy, while 126 (86.9%) chose termination. There were no differences between groups in parity, sonographic findings, insurance status, or race at the time of diagnosis. However, patients who chose termination were significantly older and earlier in gestation than those electing to continue their pregnancy. When Down syndrome is diagnosed prenatally, the choice of termination is related to maternal age and gestational age, but only gestational age is a significant independent predictor of pregnancy termination.

    Title Ontogeny of Clenched-hand Development in Trisomy 18 Fetuses: A Serial Transabdominal Fetoscopic Observation.
    Date May 1999
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Malpositioning of the fingers is a characteristic anomaly in fetuses with trisomy 18. The defect results in part from muscle variations along the radial margin of forearm and hand, absence of the thenar muscles, anomalous tendons and attachments among the forearm groups, and fusions among the arm flexor group. These variations result in radial or ulnar displacement of the tendons of extensor digitorum and digiti minimi, with overlapping of the fourth and fifth fingers radially and second finger in an ulnar direction. The ontogeny of these changes is unknown. We performed serial transabdominal thin-gauge fetoscopy in a patient with increased nuchal thickening at 12 weeks of pregnancy at the time of genetic testing and again at 14 weeks at the time of termination of pregnancy. Changes in the positioning of the fingers were not apparent at 12 weeks, but were evident at 14 weeks. The findings were beyond the resolution of ultrasound. We conclude that malpositioning of the fingers in trisomy 18 occurs some time between 12 and 14 weeks of gestation. Noninvasive confirmation of these findings may be possible with new and improved ultrasound imaging capabilities or perhaps with three-dimensional ultrasound.

    Title Prenatal Diagnosis of 46,xy/46,xx Mosaicism: a Case Report.
    Date May 1999
    Journal American Journal of Medical Genetics
    Excerpt

    We report on the prenatal diagnosis of a fetus with 46,XY and 46,XX cell lines with a normal male phenotype. Cytogenetic and molecular studies ruled out the possibility of maternal cell contamination and showed that all the X chromosomes present in both fetal cell lines were derived from a single maternal X chromosome. This suggests 46,XY/46,XX mosaicism.

    Title Variability of Adjustments to Indices in Determining Patient Risk in Biochemical Screening.
    Date May 1999
    Journal Fetal Diagnosis and Therapy
    Excerpt

    It has long been appreciated that the measurement of biochemical parameters for prenatal screening for neural tube defects, and later aneuploidy, is not as simple as measuring hemoglobin or hematocrit. Early in the game, it was recognized that there are gestational age curves, and that since alpha-fetoprotein (AFP), for example, is a fetal product, its distribution varies as a function of maternal plasma volume, and therefore the weight of the mother. A number of different adjustment factors have been used for AFP and other parameters for years, with varying degrees of consistency and reliability. Here we review a number of adjustments that have been used, and try to give priority to those that have been most effective. Furthermore, laboratories and programs need to be cognizant that with newer parameters being added, the specifics of requirements will vary on a case-by-case parameter basis, and optimal screening can only be achieved with the appropriate adjustments.

    Title Identification of a Gabab Receptor Subunit, Gb2, Required for Functional Gabab Receptor Activity.
    Date April 1999
    Journal The Journal of Biological Chemistry
    Excerpt

    G protein-coupled receptors are commonly thought to bind their cognate ligands and elicit functional responses primarily as monomeric receptors. In studying the recombinant gamma-aminobutyric acid, type B (GABAB) receptor (gb1a) and a GABAB-like orphan receptor (gb2), we observed that both receptors are functionally inactive when expressed individually in multiple heterologous systems. Characterization of the tissue distribution of each of the receptors by in situ hybridization histochemistry in rat brain revealed co-localization of gb1 and gb2 transcripts in many brain regions, suggesting the hypothesis that gb1 and gb2 may interact in vivo. In three established functional systems (inwardly rectifying K+ channel currents in Xenopus oocytes, melanophore pigment aggregation, and direct cAMP measurements in HEK-293 cells), GABA mediated a functional response in cells coexpressing gb1a and gb2 but not in cells expressing either receptor individually. This GABA activity could be blocked with the GABAB receptor antagonist CGP71872. In COS-7 cells coexpressing gb1a and gb2 receptors, co-immunoprecipitation of gb1a and gb2 receptors was demonstrated, indicating that gb1a and gb2 act as subunits in the formation of a functional GABAB receptor.

    Title Blockade of Smoking Satisfaction Using the Peripheral Nicotinic Antagonist Trimethaphan.
    Date April 1999
    Journal Pharmacology, Biochemistry, and Behavior
    Excerpt

    The present study was conducted to investigate the role of peripheral nicotinic receptors in mediating the rewarding effects of cigarette smoking. Twelve cigarette smokers rated cigarettes after intravenous infusion of the short-acting peripheral nicotinic receptor antagonist trimethaphan and after placebo (saline) infusions. Subjects were blinded to the infusion and cigarette conditions. Cigarette conditions included subjects' usual brand of cigarette, denicotinized tobacco cigarettes, and nicotine-injected cigarettes that had a tar delivery equal to that of the denicotinized cigarettes but with an enhanced nicotine delivery equal to that of subjects' usual brands. The latter cigarettes were rated as extremely harsh due to the high nicotine/tar ratio. Trimethaphan significantly attenuated the airway sensations associated with nicotine, and eliminated the difference in smoking satisfaction between the usual brand of cigarette and the other two cigarettes. These findings suggest that nicotinic receptors on peripheral nerve endings in the respiratory tract modulate smoking satisfaction and may be important in the maintenance of cigarette addiction.

    Title Phosphoinositide Hydrolysis in Vivo with Group I Metabotropic Glutamate Receptor Agonists.
    Date April 1999
    Journal Brain Research
    Excerpt

    The present report describes the effect of mGluR agonists and antagonists administration on phospholipase C activation by measuring accumulation of [3H] inositol monophosphates (IP) in rats pre-labeled with [3H]myo-inositol (i.c.v. 24 h pre-treatment). The levels of accumulated [3H]IP were then determined from clarified tissue homogenates using ion-exchange chromotography. Following lithium chloride treatment (10 mg/kg, s.c.), (R/S)-3, 5-dihydroxyphenylglycine (DHPG), a selective group I mGluR agonist was found to dose-dependently cause a maximal increase in the levels of [3H]IP at 0.3 to 3 micromol/8 microliter i.c.v. with lower doses resulting in less efficacious or no responses. This effect was temporal-dependent reaching a plateau at 2 h. The DHPG-induced increases in [3H]IP were most pronounced in the hippocampus where a 3- to 5-fold increase above vehicle was consistently found, but significant approximately 2-fold increases were also seen in the cerebellum, striatum and frontal cortex. The mixed group I and II agonist, (1S,3R)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (1S, 3R-t-ACPD), similarly resulted in dose-dependent increases in [3H]IP levels with doses of 1 to 3 micromol i.c.v. Furthermore, this effect was enantiomer specific since the less active 1R,3S-t-ACPD failed to alter phosphoinositol hydrolysis. Administration of the selective mGluR5 agonist (R/S)-2-chloro-5-hydroxyphenyl-glycine (CHPG) resulted in a dose-dependent increase in hippocampal but not cerebellar levels of [3H]IP, consistent with the receptor distribution of the two group I mGluRs. The Group II agonist LY354740 (1S,2S,5R,6S-2-aminobicycl[3.1.0]hexane-2,6-dicarboxylate monohydrate) and the group III agonist L-AP4 (L-(+)-2-amino-4-phosphonobutyric acid) failed to alter the levels of [3H]IP. LY341495 (2S-2-amino-2-(1S, 2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid) is a nM potent Group II antagonist. However, LY341495 has also been found to have microM potency in inhibiting mGluR1 and 5. The stimulation of [3H]PI hydrolysis by 1 micromol DHPG was dose-dependently blocked by co-administration of the mGluR antagonists, LY341495 at doses that are constant with an interaction at Group I mGluR's. Taken together these results suggest that stimulation of group I mGluRs results in measurable increases in PI hydrolysis in vivo. This method could be quite useful in determining the doses and routes of administration of agonists and antagonists that are required to interact with group I mGluRs.

    Title Molecular Cytogenetic Analysis of a De Novo 5q31q33 Deletion Associated Multiple Congenital Anomalies: Case Report.
    Date March 1999
    Journal American Journal of Medical Genetics
    Excerpt

    Interstitial deletions are relatively rare chromosomal anomalies that usually arise de novo. The data describing the phenotype associated with interstitial deletions of 5q are very limited. We describe the first case of multiple fetal anomalies, diagnosed on prenatal sonographic examination, associated with a deletion at 5q31q33. Sonographic examination at 23 weeks' gestation demonstrated growth parameters consistent with 20 weeks' gestation; a 7-mm nuchal fold; a dilated loop of bowel adjacent to the stomach suggestive of duodenal atresia; clubbing of the left foot; a narrow aorta; suspected ventricular septal defect; and placental thickening. The patient delivered a severely growth-restricted fetus and enlarged placenta at 30 weeks' gestation. The infant died neonatally.

    Title Multifetal Pregnancy Reduction.
    Date February 1999
    Journal Baillière's Clinical Obstetrics and Gynaecology
    Excerpt

    Multifetal pregnancy reduction (MFPR) has become a mainstay of infertility therapy as its development has allowed physicians to become more aggressive in treating patients resistant to more conservative therapies. Over the course of the past decade, MFPR has become practised in a limited number of tertiary specialty centres, which have improved its performance and very substantially lowered its risks. The majority of physicians performing MFPR employ a transabdominal needle injection of potassium chloride into the fetal thorax. Risks for pregnancy losses of patients starting with triplets and/or quadruplets reduced to twins have improved over the past decade and are not substantially different from those in patients whose pregnancy began as twins. There have been no substantiated risks of coagulopathies or damage to surviving fetuses.

    Title 2nd-trimester Maternal Serum Marker Results Are Not Altered by Delayed Analysis.
    Date December 1998
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: The goal of the study was to evaluate the significance of delayed laboratory analysis of maternal serum alpha-fetoprotein, beta-subunit of human chorionic gonadotropin, and unconjugated estriol for prenatal screening. METHODS: Biochemical analysis of 30 consecutive biochemical screening specimens of maternal serum alpha-fetoprotein, beta-subunit of human chorionic gonadotropin, and unconjugated estriol was performed immediately upon arrival to the laboratory, 7 days later, and again 14 days after maternal blood was drawn. Differences among the results of the three sets of biochemical studies were evaluated by one-way analysis of variance for repeated measures. RESULTS: No significant differences were found among the results of immediate assays as compared with those at a 7- or a 14-day delay for all three biochemical markers. CONCLUSIONS: Our data suggest that up to a 14-day delay in the performance of the 2nd-trimester maternal serum biochemical screening assays will not alter the results significantly. The results of maternal serum screening are, thus, clinically valid even if the laboratory assays were performed several days after maternal blood was drawn.

    Title Molecular Characterization and Expression of Cloned Human Galanin Receptors Galr2 and Galr3.
    Date December 1998
    Journal Journal of Neurochemistry
    Excerpt

    Galanin is a 29- or 30-amino acid peptide with wide-ranging effects on hormone release, feeding behavior, smooth muscle contractility, and somatosensory neuronal function. Three distinct galanin receptor (GALR) subtypes, designated GALR1, 2, and 3, have been cloned from the rat. We report here the cloning of the human GALR2 and GALR3 genes, an initial characterization of their pharmacology with respect to radioligand binding and signal transduction pathways, and a profile of their expression in brain and peripheral tissues. Human GALR2 and GALR3 show, respectively, 92 and 89% amino acid sequence identity with their rat homologues. Radioligand binding studies with 125I-galanin show that recombinant human GALR2 binds with high affinity to human galanin (K(D) = 0.3 nM). Human GALR3 binds galanin with less affinity (IC50 of 12 nM for porcine galanin and 75 nM for human galanin). Human GALR2 was shown to couple to phospholipase C and elevation of intracellular calcium levels as assessed by aequorin luminescence in HEK-293 cells and by Xenopus melanophore pigment aggregation and dispersion assays, in contrast to human GALR1 and human GALR3, which signal predominantly through inhibition of adenylate cyclase. GALR2 mRNA shows a wide distribution in the brain (mammillary nuclei, dentate gyrus, cingulate gyrus, and posterior hypothalamic, supraoptic, and arcuate nuclei), and restricted peripheral tissue distribution with highest mRNA levels detected in human small intestine. In comparison, whereas GALR3 mRNA was expressed in many areas of the rat brain, there was abundant expression in the primary olfactory cortex, olfactory tubercle, the islands of Calleja, the hippocampal CA regions of Ammon's horn, and the dentate gyrus. GALR3 mRNA was highly expressed in human testis and was detectable in adrenal gland and pancreas. The genes for human GALR2 and 3 were localized to chromosomes 17q25 and 22q12.2-13.1, respectively.

    Title Selective Termination and Elective Reduction in Twin Pregnancies: 10 Years Experience at a Single Centre.
    Date December 1998
    Journal Human Reproduction (oxford, England)
    Excerpt

    Selective termination is employed in multifetal pregnancies, in the presence of an abnormal fetus, in order to improve the prognosis of the normal fetuses. The term elective reduction is used to describe reduction in twin pregnancies for maternal medical conditions, psychological, or socioeconomic reasons. The purpose of this study was to evaluate the factors that influence outcome in such pregnancies. Eighty-two twin pregnancies underwent selective termination (n = 59) or elective reduction (n = 23) over a 10-year period. Early procedures, performed < or = 14 weeks (n = 31), had a pregnancy loss of 9.7% and a mean procedure-to-loss interval of 4.1 +/- 2.8 weeks; mean birthweight was 3299 +/- 395 g in survivors, with a mean gestational age at delivery of 38.4 +/- 2.3 weeks. In comparison, procedures performed > 14 weeks (n = 51) had a pregnancy loss of 7.8%, with a procedure-to-loss interval of 1.2 +/- 0.6 weeks. Mean birthweight was 2577 +/- 999 g, with a mean gestational age at delivery of 35.7 +/- 5 weeks. In conclusion, outcomes were more favourable among patients who underwent a first trimester procedure. The slight increase in pregnancy loss may be attributed to a higher than expected rate of spontaneous abortions in the first trimester, as manifested by the higher procedure-to-loss interval after a first trimester procedure. These facts underscore the importance of early detection of fetal abnormalities in twin pregnancies by ultrasonography and chorionic villus sampling.

    Title Age-specific Variation in Aneuploidy Incidence Among Biochemical Screening Programs.
    Date November 1998
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Our purpose was to compare the observed age-related incidence of Down syndrome in two large screening programs with the commonly quoted incidences used in biochemical screening programs. STUDY DESIGN: Data from two large prenatal screening programs were stratified in 5-year age groups. The age-related incidence of Down syndrome was compared with the commonly used incidence as reported by Cuckle. RESULTS: No significant differences were found in age-related incidences of Down syndrome in any age group between the screening groups or among women ages 15 through 29 in any of the three groups. However, for women 30 to 34 and > or = 40 years old, a trend was noted toward a higher incidence in the screening groups. For women ages 35 to 39, the observed incidence was significantly greater in the screening groups compared with the data of Cuckle. CONCLUSION: Our data suggest an underascertainment in Down syndrome risk built into the Cuckle model, particularly in high-risk patients.

    Title Centromere Sequences Localize to the Nuclear Halo of Human Spermatozoa.
    Date September 1998
    Journal International Journal of Andrology
    Excerpt

    Chromatin is organized into a series of discrete nuclear matrix-associated and non-nuclear matrix-associated domains. The non-matrix-associated domains consist of loops of DNA that are attached to the proteinaceous nuclear matrix by matrix-associated regions (MARs). Although this organization is well characterized in somatic cells, comparatively little is known of this mode of organizing the genome in the human sperm nucleus. To define this relationship, the interaction of human sperm chromatin with the nuclear matrix was assessed by fluorescence in situ hybridization using specific alpha satellite probes directed to the centromeric regions of chromosomes 13 plus 21 and 18. Hybridization of the centromeric sequences was visualized as segmented, bundled structures that extended from the nuclear core into the halo.

    Title Temporal Dependent Neuroprotection with Propentofylline (hwa 285) in a Temporary Focal Ischemia Model.
    Date September 1998
    Journal European Journal of Pharmacology
    Excerpt

    Propentofylline (HWA 285, 3-methyl-1-(5-oxo-hexyl)-7-propylxanthine) is an adenosine uptake and phosphodiesterase inhibitor that has been shown to be neuroprotective in both global and permanent focal ischemia animal models. However, to date, the efficacy of propentofylline has never been examined in an animal model of temporary focal ischemia or the 'therapeutic window' systematically examined in a focal ischemia model. The present experiments were designed to investigate these. Temporary (3 h) middle cerebral artery occlusion was accomplished by the monofilament method. Infarct volumes were determined at 24 h from 2,3,5-triphenyltetrazolieum chloride (TTC) stained coronal slices. Animals were dosed with vehicle or propentofylline at 3 mg/kg bolus and/or a 6 mg/kg per h infusion (24 h infusion) at 30 min, 1 h or 3 h post ischemia onset. Physiological monitoring on a subset of animals indicated no changes in mean arterial pressure, blood gases, blood pH, and glucose levels with either ischemia or drug treatment. Propentofylline treatment resulted in a statistically significant decrease in infarct volume when an infusion dose of 6 mg/kg per h was initiated at 30 min or when a bolus of 3 mg/kg plus an infusion dose was initiated at 1 h but not 3 h post ischemia. Therefore, propentofylline is neuroprotective in a model of temporary focal ischemia. This suggests that combination therapy with propentofylline might lead to clinical improvement beyond that which would occur with thrombolytics alone. The apparent short window of opportunity for effective dosing is consistent with the proposed mechanism of action for propentofylline.

    Title Prenatal Diagnosis of Cloacal Dysgenesis Sequence: Differential Diagnosis from Other Forms of Fetal Obstructive Uropathy.
    Date August 1998
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Cloacal dysgenesis sequence (CDS) is a rare cause of fetal obstructive uropathy (FOU). The prenatal differentiation of CDS from other FOU is important because CDS is not amenable to in utero surgical intervention in the form of vesicoamniotic shunts. We evaluated the prenatal characteristics of 8 fetuses with CDS, including a pair of monozygotic twins concordant for CDS, in order to identify features that would enable differentiation from other forms of FOU. Pathologic examination in each of the 8 fetuses confirmed characteristic features of absent anal, genital, and urinary orifices associated with a smooth perineum and abnormal phallic development. Associated abnormalities included dysplastic kidneys in 6, hydroureters in 5, intraluminal colonic calcifications in 2, and hypoplastic lungs in 5. Five of these fetuses initially presented as posterior urethral valve syndrome. Six fetuses had megacystis, and 4 underwent vesicocenteses to evaluate urinary electrolytes, all of which were in the 'poor-risk' category. Six fetuses were male and 2 female, contradicting earlier claims that CDS occurs only in females. Evaluation of candidates for in utero surgical intervention should include fetal karyotype, and CDS should be suspected in cases of FOU in whom the karyotype reveals a male fetus and sonographic evaluation demonstrates colonic calcifications or abnormal phallic development. Diagnostic microendoscopy may be of benefit in such cases.

    Title Pastoral Care Utilization Among Women Electing Pregnancy Termination for Fetal Anomalies.
    Date August 1998
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To identify determinants of requesting pastoral care (PC) at the time of pregnancy termination for fetal anomalies. METHODS: PC was provided by a hospital-based chaplain. Data were reviewed for 88 women who elected pregnancy termination. Nominal logistic regression and Kruskal-Wallis and Student t tests were used as appropriate. RESULTS: None of 37 women who underwent dilatation and curettage (D&C) or dilatation and evacuation (D&E) requested PC as compared with 40 of 51 patients who underwent prostaglandin induction of labor (p < 0.001). The decision to seek PC was related to gestational age (p < 0.001), but not to maternal age, prior termination of pregnancy, gravidity, parity, racial background, or insurance status. The gestational age was also a significant predictor of the procedure performed (p < 0.001). D&C/D&E were significantly more likely to be performed at earlier gestational ages. Women seeking PC were less likely to have experienced previous pregnancy loss or the death of a child. Among women who sought PC, 20% had experienced previous pregnancy loss or the death of a child, as opposed to 54% of women in the prostaglandin group who did not seek PC (p = 0.03). In the D&C/D&E group, the figure was 46%. CONCLUSIONS: Utilization of PC is much more frequent among women undergoing prostaglandin induction of labor than D&C/D&E. Determinants of seeking PC are related to issues congruent with choices of the termination procedure. Patients who experienced a previous pregnancy loss or the death of a child are also less likely to feel the need, or do not want, chaplaincy involvement.

    Title Mdl 101,002, a Free Radical Spin Trap, is Efficacious in Permanent and Transient Focal Ischemia Models.
    Date August 1998
    Journal Life Sciences
    Excerpt

    The present work describes the neuroprotective effects of the free radical spin trap, MDL 101,002, in models of permanent and transient focal ischemia. Permanent focal ischemia was carried out by occlusion of the distal segment of the middle cerebral artery (MCA) and CCA's in Spontaneously Hypertensive (SH) and Wistar rats. Transient focal ischemia was undertaken by occluding the origin of the MCA for 180 min by the intraluminar monofilament method in Wistar rats. With permanent distal MCA occlusion in SH rats, 100 mg/kg i.v. at 30 min post-ischemia resulted in a significant 40% reduction in infarct volume. Similarly, a 75 mg/kg bolus + 45 mg/kg-h dose of MDL 101,002 given i.v. at 5 min post-ischemia resulted in a 90% or 60% decrease in infarct volume in the mixed permanent/transient distal MCA model with Wistar rats using 120 or 180 min of CCA occlusion, respectively. When full reperfusion was established, after 180 min of occlusion in the proximal MCA model, a dose of 40 mg/kg + infusion and 75 mg/kg + infusion resulted in a significant 50% and 70% decrease in ischemic damage, respectively. MDL 101,002 is clearly an effective neuroprotective agent in all models examined. This work would suggest that this novel cyclic nitrone spin trap affords effective neuroprotection and is useful for the treatment of ischemic stroke.

    Title Fetal Gender Impact on Multiple-marker Screening Results.
    Date August 1998
    Journal American Journal of Medical Genetics
    Excerpt

    Maternal serum alpha-fetoprotein (MSAFP), human chorionic gonadotropin (hCG), and unconjugated estriol (uE3) are used in combination with maternal age to calculate the risk for Down syndrome (DS) in pregnancy. Increased levels of hCG and decreased levels of MSAFP and uE3 are consistent with an increased risk for DS. We retrospectively evaluated second-trimester maternal serum marker levels in a large cohort of patients with known normal outcomes and documented fetal gender. These included 15,428 patients who had MSAFP measurements, 11,428 patients with both MSAFP and hCG, and 6,090 patients with all three markers including uE3. MSAFP levels in patients with female fetuses were consistently lower than those with males. Conversely, hCG was higher in pregnancies with females as compared to males. No gender-related difference was noted for uE3. These results would suggest that the computed DS risk for female fetuses is higher than for males, despite the fact that the incidence of DS is similar in both genders. This information could be useful for calculating gender-specific DS risk; however, this would require ultrasonographic determination of fetal sex.

    Title Neuropathologic Findings in a Case of Ofds Type Vi (váradi Syndrome).
    Date August 1998
    Journal American Journal of Medical Genetics
    Excerpt

    Oral-facial-digital syndrome type VI (OFDS VI) or Váradi syndrome is a rare autosomal-recessive disorder distinguished from other oral-facial-digital syndromes by metacarpal abnormalities with central polydactyly and by cerebellar abnormalities. Histopathologic characterization of the cerebellar abnormalities has not been described previously. We describe the neuropathologic findings in a stillborn, 21-week estimated gestational age (EGA) male fetus diagnosed antenatally with signs of OFDS VI. Autopsy findings included: facial abnormalities, postaxial central polydactyly of the right hand, bilateral bifid toes, and absence of cerebellar vermis with hypoplasia of the hemispheric cortex. Microscopic analysis of the cerebellum demonstrated absence of the subpial granular cell layer and disruption or dysgenesis of the glial architecture. These histopathologic findings suggest that a primary neuronal or glial cell defect, rather than an associated Dandy-Walker malformation, may account for the cerebellar abnormalities in this form of oral-facial-digital syndrome.

    Title Maternal Weight Differences Do Not Explain Ethnic Differences in Biochemical Screening.
    Date June 1998
    Journal Fetal Diagnosis and Therapy
    Excerpt

    In previous work, we and others have shown that serum levels of alpha-fetoprotein, human chorionic gonadotropin, and estriol vary among the four commonly defined racial/ethnic groups seen in the United States: white, African-American, Asian, and Hispanic. We have suggested that better sensitivity and specificity could improve screening sensitivity and specificity. However, it has been argued that systematic weight differences among the groups could explain the variation. We evaluated the results from 208,257 patients having screening and found systematic weight differences. However, these differences were not as large as the racial/ethnic differences, showing that weight does not fully explain the discrepancy, and, therefore, four separate data bases give more accurate results.

    Title The Apparently Isolated Choroid Plexus Cyst: Importance of Minor Abnormalities in Predicting the Risk for Aneuploidy.
    Date June 1998
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVES: To assess the risk of aneuploidy in cases of isolated choroid plexus cysts (CPCs) and to compare the risk when associated with minor or major anomalies. METHODS: All fetuses with CPCs and known karyotype were identified. CPCs were categorized as 'isolated' or associated with minor or major sonographic anomalies. Preexisting risk factors for aneuploidy were compared between groups. The frequency of aneuploidy was compared between fetuses with isolated CPCs and those with CPCs associated with minor or major anomalies. Continuous and categorical variables were analyzed using one-way analysis of variance or chi-square as appropriate with p < 0.05 considered significant. RESULTS: One hundred and forty-nine fetuses with CPCs diagnosed at a mean gestational age of 19 weeks were identified. No significant differences in the frequency of preexisting risk factors for aneuploidy were identified between groups. Eighteen of 149 (12%) fetuses with CPCs had other sonographic anomalies; in 10 they were minor, and 2 of the 10 had abnormal karyotypes. Four of 8 fetuses with major anomalies were aneuploid. All 131 fetuses with isolated CPCs had normal karyotypes, and all aneuploid fetuses had additional anomalies. CONCLUSIONS: The overall rate of aneuploidy in patients with CPCs was 4% with no abnormal karyotypes among isolated CPCs. The presence of even minor sonographic abnormalities substantially increased the risk of aneuploidy. Isolated CPCs identified sonographically may not place the patient at risk of aneuploidy, but should prompt a diligent search for other minor or major anomalies. The finding of any other anomaly warrants consideration for karyotypic evaluation.

    Title Genetic Amniocentesis Following Multifetal Pregnancy Reduction Does Not Increase the Risk of Pregnancy Loss.
    Date May 1998
    Journal Prenatal Diagnosis
    Excerpt

    A collaborative, retrospective study of patients who had undergone multifetal pregnancy reduction (MFPR) to twins and subsequent genetic amniocentesis was performed to determine if amniocentesis increased the risk of pregnancy loss. Seventy-nine patients from three centres underwent MFPR and subsequent amniocentesis. The pregnancy loss rate was 5.06 per cent in this group. In comparison, the loss rate from a control collaborative series of patients who underwent MFPR only was 11.19 per cent, which was not statistically different. Thus, it appears that amniocentesis following MFPR is unlikely to increase the pregnancy loss rate.

    Title What Are the Ethical and Technical Problems Associated with Multifetal Pregnancy Reduction?
    Date March 1998
    Journal Clinical Obstetrics and Gynecology
    Title Effect of Adjustment of Maternal Serum Alpha-fetoprotein Levels in Insulin-dependent Diabetes Mellitus.
    Date March 1998
    Journal American Journal of Medical Genetics
    Excerpt

    Our objective was to determine the effect of the 20% upward adjustment of maternal serum alphafetoprotein (MSAFP) in patients with insulin-dependent diabetes mellitus (IDDM) on the number of patients that would be classified at increased risk for pregnancy complicated by either Down syndrome (DS) or neural tube defect (NTD). We retrospectively evaluated a database containing 63,110 patients who underwent multiple serum marker screening between 14 and 22 weeks gestation; 620 patients with IDDM had measurements of MSAFP of which 479 also had measurements of beta-HCG, allowing calculation of DS risk. Increased NTD risk was defined as MSAFP >2.5 MOM while increased DS risk was defined as a calculated risk > or =1/270. One IDDM patient delivered an infant with a NTD; it was not detected on serum screening. No infants were born with DS. Of the 620 patients with MSAFP determinations, 9 had values >2.5 MOM before adjustment. After upward adjustment, 7 additional patients were identified. Sixteen patients were identified at increased risk for DS before and after adjustment. Our data suggest that the 20% upward adjustment of MSAFP increases by 78%, the number of patients who would require further evaluation for NTD's. Although we were able to identify 620 women with IDDM who underwent serum screening for NTD, the low prevalence of NTD's did not allow us to demonstrate an increased detection rate. The effect of upward adjustment of MSAFP on the number of patients categorized at increased DS risk appears to be minimal.

    Title Combination of Elevated Maternal Serum Alpha-fetoprotein (msafp) and Low Estriol is Highly Predictive of Anencephaly.
    Date March 1998
    Journal American Journal of Medical Genetics
    Excerpt

    Increased levels of second trimester maternal serum alpha-fetoprotein (MSAFP) have long been established as a marker for neural tube defects (NTDs). In addition, decreased levels of maternal estriol in the third trimester have been reported in pregnancies with anencephalic fetuses. The purpose of this study was to evaluate whether early second trimester unconjugated serum estriol (uE3) is an independent predictor of NTDs. The study included 57,031 patients who underwent maternal serum screening with MSAFP at 14-22 weeks gestation. Of these, 23,415 also had uE3 measurements. There were 63 cases of NTD, an overall incidence of 1.1 per 1,000. Elevated MSAFP (> or =2.5 MOM) was detected in 1,346 patients, 48 of which had NTDs. Decreased uE3 (< or =0.5) was detected in 1,437 patients, 17 of which had NTDs. The incidence of NTDs was significantly higher in patients with low uE3, compared to patients with normal/high uE3 (1.15% vs. 0.09%, P < 001). Finally, 51 patients had both increased MSAFP and decreased uE3; 16 of these had NTDs, 14 of which were anencephalics. In conclusion, both elevated MSAFP and low maternal serum estriol are predictive of NTD but have a low sensitivity. The combination of abnormally elevated MSAFP and low estriol is highly predictive of NTD in particular anencephaly.

    Title The Legitimacy of Grieving: the Partner's Experience at Miscarriage.
    Date February 1998
    Journal Social Science & Medicine (1982)
    Excerpt

    Until quite recently the psychological and emotional effects of miscarriage on women were little understood. Research has now established that such effects are potentially very significant (Neugebauer and Kline, 1992; Leppert and Pahlka, 1984; Lasker and Toedter, 1991), but the role and response of the male partner has received very little attention (Cummings, 1984). When acknowledged at all, the response of the male partner has generally been perceived to be largely as a provider of emotional support to his partner during and after her miscarriage. In this study, based on personal interviews with 20 partners of women in the north of England who experienced a recent miscarriage, a complex set of thoughts, feelings and considerable confusion about appropriate behaviour is revealed, to the extent that such males might feel it necessary to deny their own feelings of grief in a double-bind situation.

    Title Concordance for Cloacal Dysgenesis.
    Date February 1998
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Monozygotic (MZ) twins concordant for cloacal dysgenesis were diagnosed at 15 weeks' gestation on ultrasound exam. The structural alterations result from abnormal morphogenesis of the cloacal membrane and contiguous anlage with resultant secondary changes. These defects are suggestive of teratogen exposure or an endogenous event early in gestation, resulting in MZ twinning and the development of a polytopic field defect.

    Title Vascular Disruption Birth Defects and History of Prenatal Cocaine Exposure: a Case Control Study.
    Date February 1998
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To test the hypothesis that prenatal cocaine exposure is associated with a 3-fold increased risk for vascular disruption among malformations. STUDY DESIGN: A retrospective case-control study was based upon >68,000 delivery records at Hutzel Hospital for a 9-year period. Ascertainment was based upon ICD-9 codes for limb defects, abdominal wall defects, and facial clefts. Transverse limb defects and gastroschisis were defined as cases, and nondisruption anomalies served as controls. Statistical analysis for history of maternal cocaine use reported during pregnancy was performed by chi(2) analysis and the odds ratio determined. RESULTS: A total of 190 cases of limb anomalies, abdominal wall defects, and cleft lips were identified after exclusion criteria. Statistical analysis was performed on the 119 cases informative for maternal cocaine use during pregnancy. Seven of 34 vascular disruption cases had cocaine exposure reported versus 12 of 85 other malformations controls. The odds ratio for cocaine exposure and vascular disruption is 1.58 (95% confidence interval = 0.55-4.47). CONCLUSION: The putative association of prenatal cocaine exposure and vascular disruption birth defects remains unresolved, but the attributable risk is very likely less than the 3-fold odds ratio previously reported.

    Title No Effect of Fetal Sex on Amniotic Fluid Alpha-fetoprotein.
    Date February 1998
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To evaluate the effect of fetal sex on the concentration of amniotic fluid alpha-fetoprotein (AF-AFP) in singletons and twins. MATERIAL AND METHODS: Amniocentesis was performed for advanced maternal age between 15 and 20 weeks of gestation. Only patients with normal karyotypes, uncomplicated gestations and normal ultrasound examination were included. AFP was measured in amniotic fluid by RIA and results, expressed as multiples of the median (MoM), were grouped according to fetal sex and were compared by t test. RESULTS: A total of 603 singleton pregnancies (294 females and 309 males) and 45 twin pregnancies discordant for sex met the inclusion criteria. The mean AF-AFP in singleton males was 1.06 vs. 1.04 MoM in singleton females. In twins, the mean AF-AFP was, respectively, 1.05 and 1.07 MoM (p > 0.05). CONCLUSION: Gender had no impact on AF-AFP in singleton or twin pregnancies, suggesting that the differential influence of sex hormones on the activity of the AFP gene is negligible.

    Title Differences in Measurements of the Atria of the Lateral Ventricle: Does Gender Matter?
    Date February 1998
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: To evaluate possible differences in measurements of the width of atria of the lateral cerebral ventricles of male and female fetuses. STUDY DESIGN: A prospectively entered database was reviewed to identify patients undergoing ultrasound examination at > 13 weeks between July 1, 1994 and June 30, 1995. Inclusion criteria included identification of fetal gender, measurement of the atria, and the absence of fetal anomalies. RESULTS: The atrial width of the lateral ventricles was statistically greater in male than in female fetuses (7.1 vs. 7.0 mm, p < 0.001). CONCLUSION: Although statistically significant, the difference between genders in the measurement of the ventricular atria is too small to be of clinical utility.

    Title Differential Increases in Afp, Hcg, and Ue3 in Twin Pregnancies: Impact on Attempts to Quantify Down Syndrome Screening Calculations.
    Date February 1998
    Journal American Journal of Medical Genetics
    Excerpt

    Since the advent of multiple marker screening (MMS) for Down syndrome (DS) risk calculations, limitations for twins have been apparent. Recent attempts have been made to extrapolate mathematically singleton risks to twins. Here we investigate the pattern of levels among AFP, hCG, and uE3 in twins. MMS screening data from 4,443 twin pregnancies were compared to those from 258,885 singletons from 14-21 weeks of gestational age during a 3-year period (1992-1994) in our laboratory. Medians were determined for singletons and twins, and the ratios of twins to singletons were derived. Median AFP levels for twins are approximately double those of singletons, but median increases for hCG and uE3 are less than double. The data were divided further by ethnic groups (white, African American, Asian, and Hispanic), among which there were significant variations in medians, but not in the ratios of twins to singletons. The increased serum levels of different markers in twins are not consistent across analytes, possibly reflecting independent development of different compartments. Such differences mean that a mere mathematical conversion of singleton DS risks would be imbalanced among the analytes and cannot be applied reasonably to twins. Ethnic-specific databases are as important in twins as they are in singletons.

    Title Mutations of Transmembrane Iv and V Serines Indicate That All Tryptamines Do Not Bind to the Rat 5-ht2a Receptor in the Same Manner.
    Date February 1998
    Journal Brain Research. Molecular Brain Research
    Excerpt

    Two mutations of the rat serotonin 5-HT2A receptor were made, expressed and examined for their ability to bind and be stimulated by certain tryptamines as well as their ability to bind antagonists. Mutation of Ser207 to an Ala (S207A) resulted in no substantial changes in binding of either 5-HT2A antagonists or agonists. In contrast, mutation of Ser239 to an Ala (S239A) resulted in significant changes in the 5-HT2A receptor with some but not all agonists and antagonists examined. Specifically, 5-HT had decreased affinity for the S239A mutated 5-HT2A receptor, showing over a 10-fold decrease in receptor-binding displacement, while still being capable of stimulating IP3 formation. However, the agonists tryptamine, 5-methoxytryptamine (5-MeOT), and N-1-isopropyl-5-methoxytryptamine; and the antagonists ketanserin, LY 86057, and LY 53857 were significantly less affected by a S239A mutation. These results suggest that while 5-HT might have a direct interaction with the Ser239 of the 5-HT2A receptor, tryptamine and 5-MeOT interact with this receptor in a different manner.

    Title Six-hour Window of Opportunity for Calpain Inhibition in Focal Cerebral Ischemia in Rats.
    Date February 1998
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    BACKGROUND AND PURPOSE: Stroke patients often experience a significant temporal delay between the onset of ischemia and the time to initiation of therapy. Thus, there is a need for neuroprotectants with a long therapeutic window of opportunity. The efficacy of a potent, central nervous system-penetrating calpain inhibitor (MDL 28,170) was evaluated in a temporary model of focal cerebral ischemia to determine the window of opportunity for intracellular protease inhibition. METHODS: An ex vivo brain protease inhibition assay established pharmacodynamic dosing parameters for MDL 28,170. Middle cerebral artery (MCA) occlusion was accomplished by advancing a monofilament through the internal carotid artery to the origin of the MCA. Postmortem infarct volumes were determined by quantitative image analysis of triphenyltetrazolium-stained brain sections. RESULTS: Maximal inhibition of brain protease activity was observed 30 minutes after injection of MDL 28,170 with an estimated pharmacodynamic half-life of 2 hours. MDL 28,170 caused a dose-dependent reduction in infarct volume when administered 30 minutes after MCA occlusion. A window of opportunity study was conducted to determine the maximal delay between the onset of ischemia and the initiation of efficacious therapy. MDL 28,170 reduced infarct volume when therapy was delayed for 0.5, 3, 4, and 6 hours after the initiation of ischemia. The protective effect of MDL 28,170 was lost after an 8-hour delay. CONCLUSIONS: These data indicate that the therapeutic window of opportunity for calpain inhibition is at least 6 hours in a reversible focal cerebral ischemia model. This protection is observed despite the lethal hypoxic and excitotoxic challenge, suggesting that calpain activation may be an obligatory, downstream event in the ischemic cell death cascade.

    Title Platelet Activating Factor-acetylhydrolase Activity Following Chorionic Villus Sampling and Amniocentesis.
    Date February 1998
    Journal Journal of the Society for Gynecologic Investigation
    Excerpt

    OBJECTIVE: Platelet activating factor (PAF) is essential for embryonic development and is a potent vasodilator. It increases vascular permeability and stimulates prostaglandin E2 (PGE2) production. Platelet activating factor-acetylhydrolase (PAF-AH), the enzyme that degrades PAF, is synthesized by decidual macrophages. The aim of this study was to test the hypothesis that chorionic villus sampling (CVS) and/or amniocentesis might cause an increase in maternal PAF-AH activity. METHODS: Maternal plasma PAF-AH activity was evaluated before and after genetic amniocentesis (N = 13) and transcervical CVS (N = 29). A control group (N = 9) was evaluated to study the effects of venipuncture. RESULTS: Chorionic villus sampling caused a significant elevation in PAF-AH activity (P < .0005). No changes were noted in PAF-AH activity in the amniocentesis or the control group. CONCLUSIONS: Chorionic villus sampling causes subclinical release of PAF-AH, possibly from the decidual macrophages. Increased PAF-AH activity might result in decreased PAF levels, which might lead to vasoconstriction in the placental circulation due to lack of the vasodilator effects of PAF and possibly PGE2. This mechanism might explain the increased risk for fetal limb reduction noted with CVS performed at very early gestational ages.

    Title The Selectivity of Mdl 74,721 in Models of Neurogenic Versus Vascular Components of Migraine.
    Date January 1998
    Journal European Journal of Pharmacology
    Excerpt

    MDL 74,721 (R)-2-(N1,N1-dipropylamino)-8-methylaminosulfonylmethyl-1,2,3,4-te trahydronaphthalene, a sulfonamidotetralin, has been found to exhibit a 10,000-fold greater potency in neurogenic versus vascular models of migraine. Sumatriptan, a relatively pure 5-HT1D/5-HT1B receptor agonist, also showed higher potency versus neurogenic inflammation. However, for sumatriptan the potency difference (100-fold) in the two pathophysiological models was less pronounced than seen for MDL 74,721. The affinity profile of MDL 74,721 at 5-HT1 receptor subtypes may in part explain its ability to differentiate these two physiological responses. MDL 74,721 demonstrated nanomolar affinity for 5-HT1A (12.7 +/- 0.3 nM) and 5-HT1D (41.3 +/- 10.9 nM) but considerably lower affinity for 5-HT1B receptors (> 1000 nM). Serotonin-like activity was seen in in vitro functional assays including inhibition of forskolin-stimulated cAMP accumulation in human 5-HT1D receptor-transfected fibroblasts or eliciting vasoconstriction in isolated human pial arteries. The intrinsic activity (relative to 5 - HT[E(Amax)]) and affinity (pD2) for the human cerebrovascular 5-HT receptors were: 5-HT (100%, 7.51 +/- 0.09), sumatriptan (94%, 6.85 +/- 0.1) and MDL 74,721 (66%, 5.70 +/- 0.23). In anaesthetised cats, treatment with MDL 74,721 resulted in a dose-related reduction in the percentage of carotid flow going through the arteriovenous anastomoses to the lungs, with an ED50 of 0.3 mg/kg i.v., the same as sumatriptan. However, in the guinea-pig neurogenic model, MDL 74,721 inhibited plasma protein extravasation with an ED50 of 0.023 microg/kg compared to 2.5 microg/kg for sumatriptan. MDL 74,721 was also effective in this model (in rats) after oral administration. In conclusion, MDL 74,721 demonstrates a preclinical profile consistent with anti-migraine efficacy. Its marked preference for inhibiting neurogenic inflammation makes this compound a useful tool for assessing the relative contribution of this pathophysiological mechanism to the human disease state.

    Title The Geriatric Gravida: Multifetal Pregnancy Reduction, Donor Eggs, and Aggressive Infertility Treatments.
    Date December 1997
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Recent technologic advances and societal acceptance have dramatically increased the use of donor eggs for infertile couples who require assisted reproductive technologies. Now many "older" couples can access assisted reproductive technologies to achieve pregnancies. We sought to evaluate the changing pattern of patients referred for multifetal pregnancy reduction as a result of donor eggs and age factors in aggressive infertility treatment. STUDY DESIGN: Patients undergoing multifetal pregnancy reduction from 1986 to 1996 were included and categorized by year groupings, age, and the use of donor eggs. RESULTS: A total of 523 patients were referred for and underwent multifetal pregnancy reduction. Before 1994, only 4 of 226 (1.8%) had received donor eggs, whereas in 1994 to 1996, 29 of 297 (9.8%) had received donor eggs (chi 2 = 12.6, p < 0.001). Eight of 9 patients aged > or = 45 years undergoing multifetal pregnancy reduction received donor eggs. There were no patients aged > or = 45 years before 1994 but 9 in 1994 to 1996. Four of 9 patients aged > or = 45 years with multifetal pregnancies chose reduction to singleton gestation. The proportions of patients aged > or = 40 years have increased from 0% to 11% in the last 8 years. CONCLUSIONS: The availability of donor eggs has dramatically increased the use of assisted reproductive technologies and subsequent use of multifetal pregnancy reduction in older patients. Older patients are more inclined to want reduction to singleton gestation; they cite parental demands, financial issues, and their ability to parent in their 60s and 70s as reasons for reduction to singleton gestation.

    Title Precise Gaussian Distribution Functions of Maternal Serum Alpha-fetoprotein and Free Beta-subunit of Human Chorionic Gonadotropin for Trisomy 21 Screening: Improved Accuracy for Patient Counseling.
    Date December 1997
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Gaussian equation curves are used to generate baseline curves against which a priori maternal age Down syndrome risks are adjusted to develop likelihood ratios for individual patients. We sought to evaluate the accuracy of these calculations, minimize the affects of outliers, and to make improvements. STUDY DESIGN: Gaussian distribution functions were used to investigate the best model for alpha-fetoprotein and free beta-human chorionic gonadotropin multiples of the median with use of nonlinear regressions. Parameters from distribution functions can be used to compute a more precise likelihood ratio for the decision logic for trisomy 21. A total of 58,297 normal cases and 348 cases of trisomy 21 were computed. RESULTS: Log normal distribution functions generated by nonlinear regression produced excellent but exaggerated goodness of fit R2 to the frequency distributions of the data. For normal cases values were as follows (in mean, SD, and R2, respectively): log alpha-fetoprotein -0.07199, 0.15681, and 0.9970; log beta-human chorionic gonadotropin -0.15203, 0.24284, and 0.9987. For trisomy 21 cases the values were (in mean, SD, and R2, respectively) for log alpha-fetoprotein -0.19303, 0.15802, and 0.9828 and for log beta-human chorionic gonadotropin 0.19996, 0.29760, and 0.9669. Distributions reconstructed with use of statistical means and SDs generated goodness of fit R2 from 0.585 to 0.914. Use of means and SDs derived from distribution functions increased the R2 to 0.855 and 0.999. The change in the model produces, at a 5% false-positive rate, a sensitivity of 57.18% (199/348). A 1 in 113 cutoff point risk is obtained and is tighter than the 1 in 251 without the distribution functions, as versus 1 in 270 by age calculations alone. CONCLUSIONS: Our data suggest that (1) normality of log transforms of alpha-fetoprotein and normality of log transforms of beta-human chorionic gonadotropin are reasonable models, (2) distribution functions can minimize the effect of outliers, which produces more realistic risk estimates, and (3) the effect of distribution functions versus standard mean and SDs cannot automatically be extrapolated to other parameters, which must be tested individually.

    Title Trisomy 21 Placentas: Histopathological and Immunohistochemical Findings Using Proliferating Cell Nuclear Antigen.
    Date December 1997
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: The cause of growth retardation in trisomy 21 and other autosomal trisomies is not known, but may be the result of defective cell proliferation, slowing of the cell cycle, or placental structural abnormalities. Abnormalities of the fetal cell cycle may be reflected in placental growth and can be detected using proliferating cell nuclear antigen (PCNA). METHODS: Twelve second-trimester and six third-trimester trisomy 21 placentas were examined histopathologically and stained immunohistochemically using antibodies to PCNA. Normal age-matched placentas were used as controls. RESULTS: The second-trimester trisomy 21 placentas all exhibited many large irregular hypovascular villi. The third-trimester trisomy 21 placentas showed two patterns: (i) many large, irregular hypovascular villi, and (ii) relatively normal-appearing villi with only a few abnormal villi and focal hypervascularity. PCNA staining was significantly greater in second-trimester placentas when compared to third-trimester placentas for both trisomy 21 and controls. There was no significant difference in PCNA staining in trisomy 21 placentas when compared to the normal age-matched controls. CONCLUSIONS: PCNA staining indicates no significant differences in proliferation between normal and trisomy 21 placentas. Trisomy 21 placentas show villus abnormalities, including hypovascularity.

    Title Congenital Abnormalities in Twins: Selective Termination.
    Date August 1997
    Journal Current Opinion in Obstetrics & Gynecology
    Excerpt

    Selective termination for an anomalous twin in discordant twin pregnancy has been a management option for nearly two decades. Using current conventional prenatal diagnostic techniques, the diagnosis of a twin gestation discordant for a congenital anomaly is commonly confirmed in the second trimester. Selective termination is thus usually a second-trimester procedure. The risks of second-trimester terminations as well as protocol choices, including indications and timing, have evolved over the years. Ethical issues regarding selective termination have developed significantly and continue to be debated.

    Title The Use of Cloned Repetitive Sequences As Hybridization Competitors to Detect Single Copy Sequences.
    Date July 1997
    Journal Genetic Analysis : Biomolecular Engineering
    Excerpt

    To suppress background hybridization due to repetitive sequence elements, competitor Alu containing clones were isolated from a subclone library of human cosmid clone hP3.1. Pre-annealing of the probe-with this competitor increased the signal well above background. In comparison, the addition of the competitor directly to both the prehybridization and hybridization solution was more effective in reducing background. This dramatically increased the signal to noise ratio of the specific hybridization event. Application to fluorescent in situ hybridization (FISH) is readily apparent.

    Title Behavioral Recovery Patterns in Rats Receiving the Nmda Receptor Antagonist Mdl 100,453 Immediately Post-stroke.
    Date July 1997
    Journal Pharmacology, Biochemistry, and Behavior
    Excerpt

    Rats were given MDL 100,453 ((R)-4-Oxo-5-phosphononorvaline) in a pre-determined neuroprotective dose consisting of a bolus of 24.8 mg/kg followed by an infusion of 1.05 mg/kg*h for 24 h (MDL group; n = 8) or saline of the same volume (SALINE group; n = 8) 30 min. after the onset of a 90 min. period of middle cerebral artery occlusion. Eight animals underwent SHAM surgery. Rats were evaluated post-operatively for 14 days using seven neurological tests, including water maze. SALINE animals exhibited a pattern of neurological impairment compared to SHAMs (poor performance in five of the six motor/reflex tests) peaking five days post-injury. Relative to the SALINE group, the MDL group exhibited significantly improved outcome on two of the tests and a pattern of improved behavior on the remainder of the battery. By day 14 post-ischemia, all groups exhibited recovery on the motor/reflex tests. Learning ability was disrupted in the SALINE group on days 17 and 18, whereas the MDL group's performance was not distinguishable from the SHAM group in the water maze. Thus, a neuroprotective dose of MDL 100,453 produced a pattern of behavioral sparing in the immediate post-ischemic days that was uniquely different than saline. The addition of behavioral outcome measures to histological neuroprotection data adds significantly to the ability to better evaluate a putative neuroprotective compound.

    Title Use of Urinary Beta-2-microglobulin to Predict Severe Renal Damage in Fetal Obstructive Uropathy.
    Date June 1997
    Journal Fetal Diagnosis and Therapy
    Excerpt

    PURPOSE: Establish a clinically relevant threshold for urinary beta 2-microglobulin (beta 2m) to predict the presence of several renal damage in fetuses with obstructive uropathies. METHODS: Retrospective review was conducted of urinary beta 2m levels, clinical outcomes, and pathological findings in 36 fetuses evaluated for presumed obstructive uropathy. Patients were divided into those free of renal injury (group 1, n = 13) and those with clinical or pathological evidence of severe irreversible renal injury (group 2, n = 23). RESULTS: Including all patients, a threshold beta 2m value of > 6 was able to predict the presence of severe renal damage with a 83% sensitivity and 71% specificity. beta 2m levels tended to decrease with increasing gestational age among those patients without renal injury (group 1), while beta 2m levels increased among those with severe renal damage (group 2). There was no difference in mean beta 2m levels in those < 20 weeks (p = 0.065) while there was a high degree of difference in those > 20 weeks of gestation (p < 0.001). In those > 20 weeks, a threshold of > 10 predicted the presence of severe renal damage with 100% sensitivity and specificity. CONCLUSIONS: Urinary beta 2m, especially in the fetus > 20 weeks, may be a clinically useful marker to detect the presence of severe renal damage due to obstructive uropathy and thus be an important adjuvant in the proper selection of fetuses for antenatal intervention.

    Title Modulation of B12 Dosage and Response in Fetal Treatment of Methylmalonic Aciduria (mma): Titration of Treatment Dose to Serum and Urine Mma.
    Date June 1997
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: Prenatally diagnosed methylmalonic aciduria (MMA) has been treated in only a few fetuses, and has been done empirically with maternally administered cyanocobalamin (B12) in attempts to ameliorate sequelae that include failure to thrive, developmental delay, dehydration, and coma. There has not been a systematic attempt to titrate doses to fetal response. We investigated the alterations in maternal dosage necessary to keep maternal plasma (MP) and urine (MU) levels of MMA in the normal range secondary to the ability of pharmacological doses of B12 to catalyze the reaction of methylmalonyl-coenzyme A to succinyl-coenzyme A. METHODS: A 28-year-old woman, with a 3-year-old son affected with MMA, underwent amniocentesis at 15 weeks which showed a normal karyotype, elevated amniotic fluid MMA, and decreased amniocyte 5'-deoxyadenosylcobalamin, propionate, and methyl-tetrahydrofolate. MP and MU MMA levels were measured biweekly. B12 doses were altered periodically according to laboratory-determined levels. RESULTS: MP and MU levels varied with gestational age and in response to increases in maternally administered B12. CONCLUSIONS: With increasing gestation, fetal, and placental size, increasing doses of B12 are necessary to maintain MP and MU levels of MMA within normal range. The data suggest that close surveillance and frequent measurements of MMA are necessary to properly titrate B12 treatment.

    Title Maternal Thyroid Function Does Not Alter Maternal Serum Alpha-fetoprotein Interpretation.
    Date May 1997
    Journal The Journal of Maternal-fetal Medicine
    Excerpt

    OBJECTIVE: Endocrine alterations of metabolism such as diabetes and obesity are known to affect maternal serum alpha-fetoprotein interpretation. Thyroid function has been questioned, e.g., because of binding globulins, but not adequately studied as to its impact upon maternal serum alpha-fetoprotein. The purpose of this study was to assess the possible effects of T4 and thyroid-stimulating hormone (TSH) on alpha-fetoprotein production, and to determine if thyroid function (hypothyroidism) alters maternal serum alpha-fetoprotein. METHODS: We evaluated maternal serum alpha-fetoprotein, T4, and TSH records of 25,551 patients, between 14 and 20 weeks' gestation, on whom both studies had been ordered by the patient's primary obstetrician to rule out maternal thyroid disease in pregnancy. Statistical analyses were performed by chi 2 and regression analysis. RESULTS: Patients were stratified according to thyroid function tests into two groups: hypothyroidism (T4 < 6.5 micrograms/dL and/or TSH > 5.0 micrograms/mL), and normal or hyperthyroidism (T4 > or = 6.5 micrograms/dL and/or TSH > or = 5.0 microU/mL). Maternal serum alpha-fetoprotein values were compared among groups for each gestational age. No significant variation or correlation of maternal serum alpha-fetoprotein and thyroid function was observed. CONCLUSIONS: Although other endocrine abnormalities are known to impact maternal serum alpha-fetoprotein values either through decreased production, decreased placental permeability, or plasma volume distribution alterations, maternal thyroid status does not interfere with proper interpretation of maternal serum alpha-fetoprotein.

    Title Gene Therapy. Is the Future Here Yet?
    Date May 1997
    Journal Obstetrics and Gynecology Clinics of North America
    Excerpt

    Despite the overwhelming number of articles on gene therapy that have been published in the last few years, there is a paucity of trials that have successfully demonstrated the clinical usefulness of this modality. The enthusiasm characterizing some of the earlier studies has given way to a more realistic approach. The next step is to develop more efficient vectors for effective targeting and persistent gene expression.

    Title Isolated Unilateral Fetal Pleural Effusion: the Role of Sonographic Surveillance and in Utero Therapy.
    Date April 1997
    Journal Fetal Diagnosis and Therapy
    Excerpt

    To discuss the necessity of close sonographic surveillance of small, isolated fetal pleural effusions as well as the selection criteria and benefits of in utero therapy utilizing thoracoamniotic shunts.

    Title Prenatal Diagnosis of Fetal Herpes Simplex Infection.
    Date April 1997
    Journal Fetal Diagnosis and Therapy
    Excerpt

    BACKGROUND: Intrauterine infection with herpes simplex virus (HSV) has been associated with a significant number of neonatal HSV infections. When these infections begin in utero, the associated morbidity is more severe, and treatment regimens may be less effective. CASE: A 24-year-old nullipara with an abnormal triple screen and multiple ultrasound abnormalities at 19 weeks' gestation underwent amniocentesis and cordocentesis. Laboratory results were consistent with HSV infection. The patient elected to terminate the pregnancy, and on postmortem examination of the fetus, evidence of disseminated disease was present. CONCLUSION: We believe that this case documents a relationship between HSV infection and findings on ultrasound that have previously been described in association with other in utero infections. We suggest that general viral cultures of the amniotic fluid be done when in utero infection is suspected.

    Title Demonstration of a Second Pharmacologically Active Promoter Region in the Ngf Gene That Induces Transcription at Exon 3.
    Date February 1997
    Journal Brain Research. Molecular Brain Research
    Excerpt

    Nerve growth factor (NGF) has been demonstrated to facilitate neurite outgrowth, rescue neurons from injury, and prevent programmed cell death in neurons. However, the therapeutic potential of NGF is limited by metabolic instability and poor CNS penetration. These limitations might be circumvented by identifying compounds which increase endogenous production of NGF in the brain. We sought to determine the site of all pharmacologically inducible promoters in the NGF gene using a differential analysis based on semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Mouse L929 cells were serum deprived and NGF mRNA was induced by treatment with phorbol 12-myristate 13-acetate (PMA), 1,25-dihydroxy-vitamin D3 (calcitriol) or horse serum. An increase in transcripts initiating at exon 1 was noted in cDNA from cells induced with all three agents. In addition, we also observed an increase in cDNA transcripts that initiate at exon 3 and do not include exons 1 and 2 (4.38 +/- 0.42, 2.56 +/- 0.05 and 3.04 +/- 0.03 fold increase over control for PMA, calcitriol and serum, respectively). Each of these increases was completely inhibited in the presence of actinomycin D, indicating that the increased levels of mRNA were due to increases in transcription and not mRNA stabilization. These results confirm the previous demonstration of a promoter for NGF near exon 1 and establish a pharmacologically inducible promoter in the NGF gene near exon 3 that could be targeted for therapeutic intervention.

    Title In Utero Sonographic Diagnosis of Vesicoureteral Reflux by Percutaneous Vesicoinfusion.
    Date February 1997
    Journal Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology
    Excerpt

    Vesicoureteral reflux affects approximately 1% of newborns. Although most affected children show only sonographic evidence of renal pelvic dilatation, others may show overt hydronephrosis, indistinguishable from that seen in fetuses with obstructive uropathy. Hydronephrosis secondary to fetal vesicoureteral reflux cannot be differentiated on ultrasound examination from that resulting from lower obstructive uropathy with or without reflux. As renal damage from vesicoureteral reflux may occur in up to 70% of cases, early identification and possible in utero treatment of these fetuses may be warranted. We report a sonographic technique, vesicoinfusion, for diagnosis of vesicoureteric reflux in utero. The accurate identification of vesicoureteral reflux in utero may have important diagnostic, prognostic and therapeutic implications.

    Title Smooth Muscle Development in the Obstructed Fetal Bladder.
    Date February 1997
    Journal Urology
    Excerpt

    OBJECTIVES: To evaluate changes in the smooth muscle and connective tissue development in the obstructed and normal fetal bladder. METHODS: The smooth muscle and connective tissue composition of 19 fetal urinary bladders, including those of 9 fetuses with anatomic obstruction and 10 controls free of urologic disease, were analyzed by light microscopy and computer-assisted color image analysis. RESULTS: The bladder wall thickness was markedly increased in obstructed fetuses throughout gestation as compared with that in controls. The disparity in bladder wall thickness increased rapidly during gestation. The percent area density of smooth muscle and connective tissue as well as the ratio of smooth muscle to connective tissue remained the same in the obstructed and normal control fetal bladders. CONCLUSIONS: Although bladder outlet obstruction is associated with a marked increase in bladder wall thickness, the percent of smooth muscle and connective tissue comprising the mural histology remains relatively constant as compared with that of normal fetal controls. This study suggests that bladder outlet obstruction in the fetus is not associated with excess collagen deposition but rather with an increased amount of bladder with normal cellular content and a concomitant increase in smooth muscle development.

    Title In Utero Fetal Urine Analysis and Renal Histology Correlate with the Outcome in Fetal Obstructive Uropathies.
    Date February 1997
    Journal Fetal Diagnosis and Therapy
    Excerpt

    We evaluated 8 second-trimester fetuses who had undergone termination because of obstructive uropathies and correlated the renal histopathology with fetal urine biochemical prognostic parameters. Prenatal evaluation included serial vesicocentesis, karyotyping, and sonography. According to the urinary biochemical parameters, 3 fetuses were classified to be in the good prognostic category, 2 in the borderline prognostic category, and 3 in the poor prognostic category. The kidneys were evaluated both grossly and microscopically for hydronephrosis, pelvicaliceal dilatation, cystic changes and fibrosis. Fetuses in the poor prognostic category had severely damaged renal architecture, microcysts, macrocysts, and extensive fibrosis. Fetuses in the good prognostic category had minimal histopathologic changes with preservation of the architecture. Fetuses in the borderline category showed a moderate degree of renal damage but with focally preserved architecture. We conclude (1) that there is a direct correlation between elevation in urinary electrolytes and proteins and extent of underlying renal histopathological damage and (2) that appropriate detailed prenatal evaluation of the renal function can identify fetuses who could potentially benefit from in utero therapy.

    Title Widespread Hiv Counseling and Testing Linked to a Community-based Tuberculosis Control Program in a High-risk Population.
    Date January 1997
    Journal Bulletin of the Pan American Health Organization
    Excerpt

    The aim of the work reported here was to evaluate community-wide screening for HIV infection that was linked to a tuberculosis control program in a population at high risk for both infections. Between May 1990 and August 1992, adults in Cité Soleil, Haiti, were recruited by community health workers at their homes and in clinics for individual, clinic-based counseling and testing for HIV and tuberculosis. All of the screened subjects were offered post-test HIV counseling. Those with active tuberculosis received treatment, while those with latent tuberculosis and HIV infection were offered an opportunity to participate in a trial of antituberculosis chemoprophylaxis. The 10,611 individuals screened for HIV represented 10.0% of the adult population in Cité Soleil. HIV infection was detected in 1,629 (15.4%) and active tuberculosis in 242 (2.3%). Latent M. tuberculosis infection was found in 4,800 (67.5%) of 7,309 community residents who completed tuberculosis screening, 781 (16.3%) of whom were coinfected with HIV. The high prevalence of HIV infection found in this screened population, as compared to other groups undergoing HIV screening in the same community, suggests that people at high risk for HIV infection selectively sought or accepted tuberculosis clinic screening. Also, many people with active tuberculosis were identified earlier in the course of their disease than they would have been in the absence of a screening program. Overall, the results indicate that community-based screening for HIV infection within a tuberculosis control program can result in effective targeting of screening for both infections.

    Title Studies on the Mechanism of P-chloroamphetamine Neurotoxicity.
    Date January 1997
    Journal Biochemical Pharmacology
    Excerpt

    Studies were conducted to investigate the sensitivity of p-chloroamphetamine (PCA)-induced neurochemical changes to various pharmacological manipulations known to block the neurochemical effects of 3,4-methylenedioxymethamphetamine (MDMA). The monoamine oxidase-B (MAO-B) inhibitor L-deprenyl (2 mg/kg) given 4 hr before a nonneurotoxic dose of PCA (2 mg/kg) was shown not to alter the amount of [3H]paroxetine bound to serotonin (5-HT) uptake sites 7 days after treatment. L-Deprenyl 4 hr before a neurotoxic dose of PCA (10 mg/kg) did not change the acute hyperthermia. Further, neither L-deprenyl nor another selective MAO-B inhibitor, MDL-72,974 (1.25 mg/kg), given 30 min before or daily for 4 days before a single dose of PCA attenuated or potentiated the decrease in the number of [3H]paroxetine binding sites measured 7 days after PCA treatment. The combination of the MAO-A inhibitor clorgyline (2.5 mg/kg) or a nonspecific dose of L-deprenyl (10 mg/kg) with the selective 5-HT releasing agent 5,6-methylenedioxy-2-aminoindan did not lead to changes in the levels of 5-HT, 5-hydroxyindoleacetic acid or dopamine 7 days after treatment. Finally, the 5-HT2A receptor antagonist MDL-11,939 (5 mg/kg) did not protect against the neurotoxicity of PCA. By comparing the present work with previous studies of MDMA, these results can be interpreted to suggest that the mechanism of the neurotoxicity induced by PCA is not identical to that induced by MDMA. The relationship of these results to the neurotoxicity induced by MDMA is also discussed.

    Title In Utero Percutaneous Umbilical Cord Ligation in the Management of Complicated Monochorionic Multiple Gestations.
    Date December 1996
    Journal Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology
    Excerpt

    The study was designed to report our experience with in utero percutaneous umbilical cord ligation for selective feticide in pre-viable, abnormal, monochorionic multiple gestations. The selection criteria prior to offering percutaneous umbilical cord ligation included normal anatomy in the other fetus(es), normal karyotype and polyhydramnios, or uterine contractions. The procedure was performed under combined endoscopic and sonographic guidance. Fifteen patients were referred for evaluation and possible treatment. Two patients were excluded because of misdiagnosis. The mean gestational age at the time of the procedure was 21 weeks (range 16-25 weeks). There were ten acardiac twins, one discordant twin with acrania, and two cases of twin-twin transfusion syndrome with a hydropic twin. Percutaneous umbilical cord ligation was accomplished in 11/13 (84%) cases. An average of 8.5 weeks (range 0-18.5 weeks) was gained after percutaneous umbilical cord ligation, and five of 11 patients delivered at or after 30 weeks. Seven of 11 patients undergoing ligation procedures had living children. Premature rupture of membranes occurred within 3 weeks in 4/13 (30%) of cases. In utero fetal demise remote from the procedure occurred in three ligated patients undergoing ligation, in two of which intraoperative bleeding occurred. One fetus with cystic fibrosis died in the newborn period. Percutaneous umbilical cord ligation is an evolving alternative technique for the management of abnormal monochorionic multiple gestations. The advantages of percutaneous umbilical cord ligation over other approaches include complete extravascular interruption of the blood flow in all vessels of the cord. This may prevent postmortem feto-fetal hemorrhage or possible embolic phenomena that may result in death of the normal twin, as seen with intravascular techniques. Percutaneous umbilical cord ligation prior to spontaneous death of a co-twin may also avert the neurological and other complications that may occur in the surviving twin. Technological advances should decrease the observed complications and improve the success rate of the procedure.

    Title In Utero Endoscopic Devascularization of a Large Chorioangioma.
    Date December 1996
    Journal Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology
    Excerpt

    Clinically significant chorioangiomas, i.e. those greater than 4 cm in diameter, are associated with an overall fetal loss rate of approximately 40%. Maternal complications may also be present. Most patients diagnosed with chorioangiomas have been managed expectantly. A patient with a large chorioangioma was referred to our institution, with a fetus that was hydropic and showed sonographic signs of over heart failure. Fetal anemia, marked erythropoiesis and hypoalbuminemia were documented on cordocentesis. The blood supply to the mass consisted of an artery and a vein of 9 mm in diameter. The vascular supply to the tumor was ablated via operative fetoscopy by suture ligation of the arterial supply, after subchorionic dissection of the vessel. The remaining blood supply was electrocoagulated with bipolar cautery. Although the procedure was technically successful, the fetus died on the 3rd postoperative day. This case illustrates ablation of the blood supply of placental chorioangiomas as a potential management alternative for those patients with large chorioangiomas. Early identification and treatment may result in a successful outcome.

    Title Ethical Issues Surrounding Multifetal Pregnancy Reduction and Selective Termination.
    Date December 1996
    Journal Clinics in Perinatology
    Excerpt

    MFPR and selective terminations satisfy the criteria of enabling pregnancies to continue with the least harm and most benefits to all involved. The surviving infants can be saved from certain death (abortion) or higher risks of severe harm and death and of an extended stay in neonatal intensive care (premature delivery). In the hands of trained operators, MFPR and selective termination is, in our opinion, the best means to protect the mother's health and well-being, given it is available and approved by the parents. MFPR and selective termination avoid the trauma of abortion of a wanted pregnancy, enable the parents to achieve the goal of having their own child, and avoid the dangers of delivery of multiple premature infants. There is no doubt that any procedure that involves the death of a fetus will be hotly argued despite the potential for greater good. We acknowledge that it will be impossible to convince those who cannot morally accept the taking of any life regardless of the circumstances. We hope, however, that we have shown there is a place for MFPR and selective termination in a very limited number of circumstances and the ethical probity of MFPR and selective termination as an option in such cases.

    Title [3h]mdl 100,907: a Novel Selective 5-ht2a Receptor Ligand.
    Date December 1996
    Journal Naunyn-schmiedeberg's Archives of Pharmacology
    Excerpt

    In studies using standard radioligands, unlabeled MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol) has been shown to have a high degree of selectivity for the 5-HT2A receptor. The present study was undertaken to investigate the receptor binding characteristics of [3H]MDL 100,907 in rat cortical homogenates. [3H]MDL 100,907 was found to reach equilibrium at 37 degrees C after 15 min. Saturation experiments indicated binding to a single site with a KD of 0.56 nM, Hill slope of 1.15, and a Bmax of 512 fmol/mg protein. In parallel experiments with the standard 5-HT2A receptor radioligand, [3H]ketanserin, with prazosin added to block alpha 1 receptors, a similar Hill slope and Bmax was noted but a two-fold higher KD was found. In competition binding studies using 0.5 nM [3H]MDL 100,907, some 19 standard ligands to various receptors including the 5-HT1A, D2, alpha 1, and sigma receptors resulted in estimated KI values that were consistent with [3H]MDL 100,907 selectively binding to the 5-HT2A receptor. A comparison of the KI values for 17 standard 5-HT2A receptor agonists and antagonists displacing [3H]MDL 100,907 versus [3H]ketanserin resulted in a highly significant linear correlation (R2 = 0.96, P < 0.001). Taken together these results suggest that [3H]MDL 100,907 is binding to the 5-HT2A receptor with a sub-nanomolar affinity without the use of secondary blocking agents.

    Title Treatment of X-linked Severe Combined Immunodeficiency by in Utero Transplantation of Paternal Bone Marrow.
    Date December 1996
    Journal The New England Journal of Medicine
    Title Six-month Supervised Intermittent Tuberculosis Therapy in Haitian Patients with and Without Hiv Infection.
    Date December 1996
    Journal American Journal of Respiratory and Critical Care Medicine
    Excerpt

    We enrolled 427 consecutive patients with tuberculosis diagnosed in Cité Soleil, Haiti in a trial of short-course intermittent therapy. All patients received supervised therapy with isoniazid, rifampin, pyrazinamide, and ethambutol thrice weekly for 8 wk, followed by isoniazid and rifampin thrice weekly for 18 wk. At entry, the 177 human immunodeficiency virus (HIV)-infected patients (42%) were found significantly more likely to have extrapulmonary tuberculosis and negative tuberculin skin tests (p < 0.05). Treatment was well tolerated by both groups of patients, and adherence to the treatment regimen was over 90%. Among patients with pulmonary or intrathoracic tuberculosis, 9% of HIV-seropositive and 1% of HIV-seronegative patients died during therapy (p < 0.001), whereas 81% and 87%, respectively, of those in the two groups were cured. Relapses occurred in 5.4% of HIV-seropositive and 2.8% of HIV-seronegative patients who completed treatment (p = 0.36). Survival after tuberculosis was poorer in HIV-seropositive patients, whose probability of dying was 33% at 18 mo after diagnosis as compared with 3% for HIV-seronegative patients (p < 0.001). HIV-seropositive patients who died had significantly lower median CD4 lymphocyte counts than did HIV-seropositive patients who survived (p < 0.001). Treatment of tuberculosis with short-course, thrice-weekly, supervised therapy in the setting of a developing country is highly efficacious in both HIV-seropositive and -seronegative patients.

    Title Faint and Positive Amniotic Fluid Acetylcholinesterase with a Normal Sonogram.
    Date December 1996
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Both faint and positive amniotic fluid acetylcholinesterase determinations have been associated with fetal abnormalities. We evaluated the effect of a normal sonogram and positive or faint acetylcholinesterase level on the risk for anomalies. STUDY DESIGN: Between Jan. 1, 1989, and Feb. 1, 1995, 4859 amniocenteses were performed. Twenty-three cases of abnormal acetylcholinesterase determinations combined with normal sonograms were identified, and pregnancy outcomes were determined. RESULTS: One abnormal karyotype was identified (45,X/47,XXX mosaic). No neural tube defects were seen in infants with an abnormal acetylcholinesterase determination and normal sonogram. One fetus of a twin pregnancy had a ventral wall defect that was not detected on ultrasonography. Seventy-three percent of infants were normal at birth, but 27% of the pregnancies had abnormal outcomes. CONCLUSIONS: Advances in ultrasonography have led to improved detection of fetal abnormalities. With a normal karyotype, repeat invasive testing may not be necessary.

    Title Correction of Hemodynamic Abnormalities by Vesicoamniotic Shunting in Familial Congenital Megacystis.
    Date December 1996
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Vesicoamniotic shunting is typically reserved for treatment of fetal obstructive uropathy. We report a case of congenital megacystis without anatomic urinary obstruction in whom a vesicoamniotic shunt was used to improve fetal hemodynamics as measured by Doppler velocimetry.

    Title International, Collaborative Experience of 1789 Patients Having Multifetal Pregnancy Reduction: a Plateauing of Risks and Outcomes.
    Date October 1996
    Journal Journal of the Society for Gynecologic Investigation
    Excerpt

    To develop the most up-to-date, complete data base of multifetal pregnancy reduction (MFPR) from cases, and to provide the best counseling for couples with multifetal pregnancies.

    Title Fetal Therapy for Obstructive Uropathy: Diagnosis Specific Outcomes [corrected]
    Date August 1996
    Journal The Journal of Urology
    Excerpt

    PURPOSE: Attempts to evaluate prenatal vesico-amniotic shunt therapy have been hampered by inconsistencies in patient selection, treatment and termination criteria, and outcomes measurement. Outcomes have generally been measured against those of patients with postnatally detected posterior urethral valves. The purpose of this report was to evaluate the influence of the underlying diagnosis on the clinical outcomes of fetuses undergoing evaluation for prenatal intervention for suspected obstructive uropathy. Furthermore, specific outcomes diagnosis was compared to the published natural history of these disorders to begin to establish a basis for measuring the efficacy of prenatal intervention. MATERIALS AND METHODS: We retrospectively reviewed the outcomes of 55 consecutive patients undergoing prenatal evaluation using structured outcome measures stratified by specific diagnoses to provide a comparison to the reported natural history for each underlying disorder. RESULTS: All fetuses had early onset of oligohydramnios/anhydramnios representing the worst end of the spectrum. Compared to postnatally diagnosed patients, prenatally diagnosed patients with posterior urethral valves had lower survival (60 versus 93%) but similar postnatal renal failure rates (31 versus 33%). Cases of prenatally detected but untreated posterior urethral valves had a 44% renal failure rate. In fetuses with the prune-belly syndrome survival (86 versus 72%) and renal function rates (17 versus 27% renal failure) compared favorably with the postnatal experience, although 55% of the cases had significant urethral obstruction. All patients with urethral atresia died. CONCLUSIONS: The underlying etiology of obstruction appears to have a marked influence on clinical outcome independently of treatment. When evaluated by specific diagnosis, intervention appears to provide outcomes in these high risk fetuses that are comparable to those for disease detected postnatally. Interpretation of series that do not distinguish cases by onset, severity and specific pathological process is problematic. Greater standardization of patient selection, treatment and outcome measurement, including the use of specific diagnoses, is necessary to allow an accurate assessment of the efficacy and proper role of fetal therapy.

    Title Persistence of Partial Molar Placenta and Severe Preeclampsia After Selective Termination in a Twin Pregnancy.
    Date August 1996
    Journal Obstetrics and Gynecology
    Excerpt

    BACKGROUND: Triploid molar pregnancies are usually managed by evacuation of the uterine contents. CASE: A 25-year-old woman had a clomiphene citrate-induced twin pregnancy. Ultrasound scan at 13 weeks revealed one anomalous twin. Cytogenetic analysis revealed a karyotype of 69, XXY and a normal other twin. In an attempt to salvage the normal fetus, selective termination was successfully performed at 15 weeks by intracardiac potassium chloride injection. However, the placenta continued to grow and severe preeclampsia developed at 19 weeks, requiring pregnancy termination. CONCLUSION: Selective termination of a triploid twin does not guarantee resolution of molar growth and sequelae of the mole; severe preeclampsia can still develop.

    Title Integration of Genetics and Ultrasonography in Prenatal Diagnosis: Just Looking is Not Enough.
    Date August 1996
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: There has been a gradual shift of the focus of prenatal diagnosis from genetics to ultrasonography. We assessed our primary genetics approach to determine what would be missed without the genetics component. STUDY DESIGN: We evaluated referral indications for patients with normal and abnormal prenatal findings from Jan. 1, 1990, to March 31, 1995, and categorized them according to type of fetal anomalies and genetic abnormalities found. Discordance among initial indication, identified risk factors, and observed abnormalities was assessed. RESULTS: The proportion of patients referred for very-high-risk indications increased over time; 13.5% of all patients (1992 of 14,725) had abnormalities. Abnormal outcomes were categorized as 26% chromosomal, 58% ultrasonographic dysmorphologic features, 11% biochemical or deoxyribonucleic acid disorders, 5% infectious, and 11% other. Of the cases of ultrasonographic dysmorphism (exclusive of the aneuploidies), 3.5% were ultimately determined to be syndromic and 2.5% to be discrepant, that is, having a different abnormality than the referred diagnosis. Including the whole spectrum of disorders seen, half of the abnormalities would not be detectable with even high-quality ultrasonography. CONCLUSION: A large number of abnormal findings were not consistent with initial indication for referral. Correct diagnosis depended on increased acuity provided by genetic pedigree analysis and recognition of syndromes. Diligence in the search for associated anomalies, aneuploidy, pedigree analysis, and syndromic abnormalities remain critical components in the differential diagnosis. The elucidation of unexpected findings suggests the advantages of early counseling and a genetics-based approach combined with tertiary rather than primary ultrasonography with counseling only when anomalies are detected.

    Title Preclinical Characterization of the Potential of the Putative Atypical Antipsychotic Mdl 100,907 As a Potent 5-ht2a Antagonist with a Favorable Cns Safety Profile.
    Date June 1996
    Journal The Journal of Pharmacology and Experimental Therapeutics
    Excerpt

    In preclinical studies, [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4- piperidinemethanol] [formula: see text] (MDL 100,907), a putative atypical antipsychotic, was characterized in vitro as a potent and selective ligand for the serotonin2A (5-HT2A) receptor and was evaluated in vitro and in vivo as a potent 5-HT2A receptor antagonist. Furthermore, MDL 100,907's potential CNS safety profile and selectivity as a potential antipsychotic agent were evaluated and compared with benchmark compounds. MDL 100,907 demonstrated low nanomolar or subnanomolar binding in vitro at the 5-HT2A receptor and showed a > 100-fold separation from all other receptors measured. MDL 100,907 had subnanomolar potency as a 5-HT2A antagonist in vitro in reversing 5-HT-stimulated inositol phosphate accumulation in NIH 3T3 cells transfected with the rat 5-HT2A receptor. In vivo, MDL 100,907 potently inhibited 5-methoxy-N, N-dimethyltryptamine-induced head twitches in mice or 5-hydroxytryptophan-induced head twitches in rats. In vivo functional tests in mice revealed a > 500-fold separation between doses that produced 5-HT2A antagonism and doses that produced alpha 1-adrenergic or striatal D2 antagonism. Using inhibition of D-amphetamine-stimulated locomotion in mice as a measure of potential antipsychotic efficacy, MDL 100,907 showed a superior CNS safety index relative to the reference compounds, haloperidol, clozapine, risperidone, ritanserin, and amperozide, in each of five tests for side effect potential, including measures of ataxia, general depressant effects, alpha 1-adrenergic antagonism, striatal D2 receptor antagonism, and muscle relaxation. MDL 100,907 did not antagonize apomorphine-induced stereotypes in rats, suggesting that it potentially lacks extrapyramidal side effect liability. MDL 100,907 showed selectivity as a potential antipsychotic in that it lacked consistent activity in selected rodent models of anticonvulsant, antidepressant, analgesic, or anxiolytic activity. In summary, these preclinical data indicate that MDL 100,907 is a potent and selective ligand at the 5-HT2A receptor. MDL 100,907's potent 5-HT2A antagonist activity might account for its activity in preclinical models of antipsychotic potential. Ongoing clinical evaluation with MDL 100,907 will test the hypothesis that 5-HT2A receptor antagonism is sufficient for antipsychotic activity in humans.

    Title Modified Stylet Technique for Tenting of Amniotic Membranes.
    Date April 1996
    Journal Obstetrics and Gynecology
    Excerpt

    A modified amniocentesis technique can reduce the failure rate in cases of tenting of the membranes. Failure to aspirate amniotic fluid (AF) because of amniotic membrane tenting may persist after advancement and rotation of the needle. In such cases, the membranes may be pierced by using a stylet that is longer than the length of the needle. With the needle in the middle of a suitable AF pocket, the stylet of the needle is replaced with a longer stylet. Under real-time ultrasonographic guidance, the tip of the stylet is then rapidly advanced 5-10 mm beyond the tip of the needle. During genetic amniocentesis, we have used the longer stylet technique to pierce tented membranes without complications in 21 of 22 cases.

    Title Prenatal Cytogenetic Abnormalities: Correlations of Structural Rearrangements and Ultrasonographically Detected Fetal Anomalies.
    Date December 1995
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Our purpose was to determine the distribution of karyotypic abnormalities detected at prenatal diagnosis, fetal anomalies, and ability for fluorescent in situ hybridization detection. STUDY DESIGN: Our cytogenetic database from January 1988 to April 1994 was categorized according to type and potential detection by current standard fluorescent in situ hybridization probes. Fetal anomalies and cytogenetic aberrations were compared. RESULTS: A total of 664 cases of abnormal fetal karyotypes were identified from 12,454 prenatal cytogenetic cases (7529 amniocenteses and 4925 chorionic villus sampling) and were classified as autosomal aneuploidy (331), sex aneuploidy (103), polyploidy (38), marker aneuploidy (19) and structural rearrangements (173). Standard fluorescent in situ hybridization probes would have missed 31% of the abnormal cases: 90 aneuploidy, 14 de novo marker aneuploidy, and 65 de novo structural aberrant cases. The 134 cases of structural chromosomal rearrangements with complete ultrasonographic records were further classified as polymorphism (42), familial (43), or de novo (49). Frequency of fetal anomaly detection by ultrasonography in de novo cases (22/49) was higher than other rearrangements (chi 2 7.4, p = 0.006). CONCLUSION: The contribution of unusual aneuploidies (16%) and structural chromosomal rearrangements (26%) in prenatal diagnostic practice is significant. Fetal anomalies were detected by ultrasonography in 45% of the de novo rearrangement cases. Fluorescent in situ hybridization would miss 31% of the abnormal cases.

    Title The Choices Women Make About Prenatal Diagnosis.
    Date November 1995
    Journal Fetal Diagnosis and Therapy
    Title Computer-generated Admission Forms Have Greater Accuracy.
    Date October 1995
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    We examined the accuracy of computer-generated admission forms to standardized handwritten admission forms for 40 patient records. There was a mean of 8.3 errors among handwritten forms but only 0.9 errors among computerized forms (p < 0.0001). Written forms had seven serious errors versus one for computerized forms (p < 0.05). We conclude that computerized admission forms have superior accuracy.

    Title In-utero Percutaneous Cystoscopy in the Management of Fetal Lower Obstructive Uropathy.
    Date October 1995
    Journal Lancet
    Excerpt

    In fetuses with lower obstructive uropathy, sonography cannot establish the cause of obstruction. We assessed whether percutaneous fetal cystoscopy could be useful in the evaluation and treatment of obstructive defects in utero. We inserted a fibreoptic endoscope through the lumen of the needle or trocar into the fetal bladder at the time of vesicocentesis or vesicoamniotic-shunt placement and looked at the the urethra, bladder neck, and ureteral orifices. Urethral vesicoamniotic shunting was considered in suitable cases; otherwise a percutaneous shunt was inserted. Fetal cystoscopy was possible in 11 of 13 patients referred. The bladder mucosa appeared haemorrhagic or oedematous in three. The ureteral orifices were seen in 9/11 fetuses, dilation was seen in five, but was only suspected in two by ultrasound. Ureteral webs were noted in two other fetuses. Two of seven fetuses underwent urethral vesicoamniotic shunting; urethral patency was achieved with urethral probing alone in one fetus. The remaining four fetuses were shunted with a standard technique. Fetal cystoscopy helps define the underlying conditions responsible for sonographic findings of lower obstructive uropathy, and allows the introduction of new treatments.

    Title Endoscopically Assisted, Ultrasound-guided Fetal Muscle Biopsy.
    Date September 1995
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Direct endoscopic visualization of in utero fetal muscle biopsy was performed in 2 cases for which the primary guidance for the procedure remained real time ultrasound. Direct visualization aids in the precise placement of the biopsy gun which may enable the procedure to be done at earlier gestational ages. At the currently used gestational ages (i.e. 18+ weeks), it does not substantially improve the procedure.

    Title Sequential Urinalysis Improves Evaluation of Fetal Renal Function in Obstructive Uropathy.
    Date September 1995
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVES: The purpose of our study was to determine whether sequential vesicocenteses improve the evaluation of renal damage, compared with single urine sampling in obstructive uropathy. STUDY DESIGN: A total of 29 fetuses with complete obstructive uropathy underwent a minimum of three sequential complete vesicocenteses at 48- to 72-hour intervals. First and last urine values were analyzed for multiple parameters. The ability of first versus last urine values to detect the presence of renal damage was compared according to postnatal or fetal autopsy information. RESULTS: Fetuses with minimal renal damage had patterns of decreasing hypertonicity and last urine values below cutoff thresholds indicative of favorable prognosis. Fetuses with significant renal damage had higher initial values and patterns of increasing hypertonicity. For five of six parameters, last urine samples were more predictive of renal damage than first urine samples. CONCLUSION: Last urine values together with pattern-of-change trend analysis after serial vesicocenteses improve diagnostic precision in fetuses with complete obstructive uropathy.

    Title In Utero Fetal Muscle Biopsy Alters Diagnosis and Carrier Risks in Duchenne and Becker Muscular Dystrophy.
    Date July 1995
    Journal Fetal Diagnosis and Therapy
    Excerpt

    We have previously shown that Duchenne muscular dystrophy (DMD) can be diagnosed by fetal muscle biopsy and immunohistochemical staining showing the absence of dystrophin. In Becker muscular dystrophy (BMD), there is a variable dystrophin staining pattern.

    Title Evolving Patterns of Iatrogenic Multifetal Pregnancy Generation: Implications for Aggressiveness of Infertility Treatments.
    Date July 1995
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Our purpose was to assess the changes in multifetal pregnancy generation as a function of utilization of ovulation stimulation and assisted reproductive techniques and to document the relative control of hyperstimulation between the methods. STUDY DESIGN: The methods of infertility treatment, number of fetuses, and outcomes of 220 patients referred for multifetal pregnancy reduction were compared over three time periods (1986 to 1989, 1991 to 1992, and 1992 to 1993). Clomiphene, human menopausal gonadotropin, and ovulation stimulation with urofollitropin were compared against gamete intrafallopian transfer, zygote intrafallopian transfer, and in vitro fertilization (assisted reproductive techniques). RESULTS: The proportion of multifetal pregnancies generated by assisted reproductive techniques has steadily risen from 26% in the first two time periods to nearly half in the last 2 years. However, the number and proportion of quintuplet and greater pregnancies from assisted reproductive techniques have steadily fallen while for ovulation stimulation the proportion has remained about one third. CONCLUSION: Despite considerably increased use and proportionate generation of triplet and quadruplet pregnancies, the incidence of quintuplets has fallen for assisted reproductive techniques while there has been no improvement for ovulation stimulation. Continued, greater vigilance, particularly in the use of human menopausal gonadotropin and urofollitropin, must be emphasized.

    Title Histopathology of Fetal Diastrophic Dysplasia.
    Date July 1995
    Journal American Journal of Medical Genetics
    Excerpt

    We report on three cases of diastrophic dysplasia in second trimester fetuses and discuss the differential diagnosis and clinical, radiologic, and histopathologic findings. Manifestations of typical diastrophic dysplasia in infants and older patients include abnormal pinnae, scoliosis, and joint contractures; these were absent in the fetuses, in keeping with the tendency for the clinical and radiologic aspects of this disease to become more severe with age. The histopathologic characteristics of the cartilage appear to be similar in the fetus and older patient, and therefore may be useful in differentiating diastrophic dysplasia from other osteochondrodysplasias in the second trimester.

    Title Predictive Value of Fetal Serum Beta 2-microglobulin for Neonatal Renal Function.
    Date June 1995
    Journal Lancet
    Excerpt

    When fetal urinary-tract malformations (UTM) are discovered, management is based on the prediction of postnatal renal function, currently made by fetal urinary biochemistry and sonography. Serum beta 2-microglobulin has been used postnatally to estimate renal function and does not cross the placenta. We investigated the relation between fetal serum beta 2-microglobulin and renal function by comparing 64 unaffected fetuses and 15 fetuses with UTM. A beta 2-microglobulin above a 5.6 mg/L cut-off gave cross-validated sensitivity of 80.0%, specificity of 98.6%, a positive predictive value of 88.9%, and a negative predictive value of 97.1% for our cohort study.

    Title Moms (multiples of the Median) and Dads (discriminant Aneuploidy Detection): Improved Specificity and Cost-effectiveness of Biochemical Screening for Aneuploidy with Dads.
    Date May 1995
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Our purpose was to assess the efficacy of double- and triple-screening paradigms for Down syndrome and to develop a more logical, statistical approach to risk prediction that will decrease the cost of screening and allow the incorporation of new parameters appropriately weighted for their contribution. STUDY DESIGN: Data from 24,504 patients who had biochemical screening for Down syndrome by single (alpha-fetoprotein), double (alpha-fetoprotein, beta-human chorionic gonadotropin), or triple screening (alpha-fetoprotein, beta-human chorionic gonadotropin, unconjugated estriol) who had complete outcome information were analyzed by (1) existing gaussian-based methods, (2) the Glasgow ratio method, and (3) a new statistical approach (i.e., directly adjusted data sets for discriminant aneuploidy detection [DADs]) RESULTS: By use of individual risk-based thresholds for "at risk" status, both double and triple screening performed far better than single screening, but the percentages of patients at risk varied widely. When the percentages at risk were held constant, the sensitivity of double and triple screenings was similar, suggesting that there are no benefits of using estriol as a third marker. For 25,000 patients the use of only alpha-fetoprotein and beta-human chorionic gonadotropin would save about $500,000, with no decrease in sensitivity. With the DADs approach a statistically sound model giving more stable estimates was developed that permits each factor to be analyzed for its own explained proportion of variance and allows each parameter to have different weighting. For this data set the same sensitivity was seen with, conservatively, a 1% reduction in the percentage of patients at risk, which would reduce by 250 the number of amniocenteses, at a further savings of about $400,000. CONCLUSIONS: By use of existing methods, double screening is equally as effective as triple screening, so that the expense of estriol is unnecessary. The DADs approach, by allowing for variable weighting of parameters, lowers the at risk percentage and will permit a much more flexible approach as new parameters become available. Changing to DADs and eliminating estriol should achieve higher specificity for the same sensitivity and save, conservatively, about $900,000 in this series. Extrapolated nationally, if confirmed, the annual savings could approach $72,000,000.

    Title Combining Humerus and Femur Length for Improved Ultrasonographic Identification of Pregnancies at Increased Risk for Trisomy 21.
    Date May 1995
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Our purpose was to evaluate the value of the combination of femur and humerus length measurements in ultrasonographic screening for trisomy 21. STUDY DESIGN: Direct necropsy measurements were analyzed on 703 midgestational fetuses (641 normal, 62 with trisomy 21). The (leg+arm length)/foot length ratio was found to be significantly shortened for fetuses with trisomy 21. On the basis of necropsy data 576 midgestational pregnancies were evaluated ultrasonographically for (femur+humerus length)/foot length ratio to identify fetuses at increased risk for trisomy 21. RESULTS: An ultrasonographic (femur+humerus length)/foot length ratio < or = 1.75 gave a 15.3 odds ratio risk for trisomy 21 in our high-risk population and correctly identified 53% of fetuses with trisomy 21, with a false-positive rate of 7%. In addition, the use of this ratio eliminates the need for gestational age-corrected nomograms and complicated calculations in ultrasonographic screening. CONCLUSION: The (femur+humerus length)/foot length ratio may be an additional effective ultrasonographic marker for identification of fetuses at increased risk for trisomy 21.

    Title Fluorescent in Situ Hybridization and Second-trimester Sonographic Anomalies: Uses and Limitations.
    Date April 1995
    Journal Fetal Diagnosis and Therapy
    Excerpt

    The critical need for rapid and reliable karyotype analysis can be no greater than in the setting of sonographic fetal anomalies. Fluorescent in situ hybridization (FISH) directly applied to interphase chromosomes can decrease the time required to identify the common aneuploidies. Our retrospective study reviewed 50 consecutive patients with sonographic fetal anomalies who underwent FISH. Within this high risk group, nonmosaic chromosomal aneuploidies were present in 16% of the fetuses (8 of 50), and 2 additional fetuses had cytogenetic abnormalities: 1 case, 46,XY,-12,+der(12)t(12;13)(p13; q14.1), and 1 case a 10% mosaic for trisomy 21. Of the 10 cytogenetically abnormal fetuses, FISH was able to identify correctly all 8 of the nonmosaic aneuploidies within 2 days of receipt of the specimen in the laboratory. Clinical decisions can be made on the basis of concordant FISH and ultrasound abnormalities, shortening the decision-making process for most of the aneuploid cases. However, our experience demonstrates some of the limitations of current FISH protocols and the continued necessity for formal karyotype analysis.

    Title Percutaneous Fetal Cystoscopy and Endoscopic Fulguration of Posterior Urethral Valves.
    Date March 1995
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Percutaneous fetal cystoscopy was performed in a male fetus with ultrasonographic evidence of lower urinary tract obstruction at 19 weeks of gestation. The diagnosis of posterior urethral valves was confirmed. Percutaneous endoscopic fulguration of the valves was successfully performed at 22 weeks of gestation, and urethral patency was established. This case illustrates the feasibility of performing diagnostic and therapeutic endoscopic procedures within the human fetus for the management of a congenital anomaly. While we believe that fetal cystoscopy may improve our diagnostic, prognostic, and therapeutic capabilities in the management of fetuses with lower obstructive uropathy, studies are needed to establish the actual value, risks, and limitations of this new approach in fetal medicine.

    Title Prenatal Diagnosis: Choices Women Make About Pursuing Testing and Acting on Abnormal Results.
    Date January 1995
    Journal Clinical Obstetrics and Gynecology
    Title Microscopic Neuroblastoma in a Fetus with a De Novo Unbalanced Translocation 3;10.
    Date January 1995
    Journal American Journal of Medical Genetics
    Excerpt

    We report on a fetus with a de novo unbalanced translocation 3;10 and a microscopic neuroblastoma. The fetus had the karyotypic and phenotypic manifestations of partial dup (3q). The finding of a constitutional chromosomal abnormality and a microscopic neuroblastoma, although possibly coincidental, supports Knudson's two hit hypothesis for development of neuroblastomas and other embryonal tumors. In this case the first mutation is represented by the constitutional abnormality, possibly resulting in the microscopic neuroblastoma. A second mutation affecting the abnormal cells, which may be more prone to mutagenesis, may trigger a neuroblastoma.

    Title Fetal Muscle Biopsy: Collaborative Experience with Varied Indications.
    Date December 1994
    Journal Obstetrics and Gynecology
    Excerpt

    To develop a fetal muscle biopsy technique for immunohistochemical diagnosis of Duchenne and Becker muscular dystrophies.

    Title Constriction of the Umbilical Cord Leading to Fetal Death. A Report of Three Cases.
    Date December 1994
    Journal The Journal of Reproductive Medicine
    Excerpt

    Constriction of the umbilical cord is characterized by localized absence of Wharton's jelly, leading to narrowing of the cord, thickening of the vascular walls and narrowing of the vascular lumens. This may result in a compromised fetal blood supply, leading to fetal anoxia and eventual fetal death. Approximately 50 cases have been reported in the world literature over the last three centuries. Three cases of umbilical cord constriction leading to intrauterine fetal demise are reported. Two of the patients presented during the late second trimester with loss of sensation of fetal movements. Intrauterine fetal demise was diagnosed, and autopsy revealed constricted umbilical cords associated with torsion. The third patient is unique in that fetal death was precipitated by a routine, technically uncomplicated, transplacental amniocentesis procedure performed in the early second trimester. At the time of termination of the pregnancy we found marked stenosis with torsion over a 1-cm segment of the umbilical cord juxtaposed against the fetal insertion site. Umbilical cord constriction is a rare, almost invariably fatal condition, usually undiagnosed antenatally. In case 3, disruption of the placenta by amniocentesis may have initiated a terminal event in a fetus already compromised by a cord constriction. Three possible mechanisms could have contributed to the fetal death after amniocentesis in the presence of cord constriction: acute vasospasm, acute oligohydramnios and uterine contraction, or an obliterating thrombus.

    Title Fluorescent in Situ Hybridization Utilization for High-risk Prenatal Diagnosis: a Trade-off Among Speed, Expense, and Inherent Limitations of Chromosome-specific Probes.
    Date November 1994
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: The development of fluorescent in situ hybridization chromosome-specific probes has allowed the use of new fetal tissue collection techniques, such as fetal cells in maternal blood and coelocentesis--both of which, with current techniques, cannot generate complete karyotypes. We evaluated chromosome-specific probes for additional potential limitations in the setting of a high-risk prenatal diagnosis center. STUDY DESIGN: The last 24 months of fetal karyotypes from our prenatal cytogenetics laboratory were analyzed for those abnormalities that should be detectable by chromosome-specific probes and those that would likely be missed. RESULTS: In 6006 karyotypes 207 (3.4%) abnormalities were found, of which 104 were common trisomies, 12 triploidies, and 19 monosomies that would have been detected with current probe combinations (13, 18, 21, X, and Y) (135/207, 65.2%). Seventy-two abnormalities (35%) represented other trisomies (16/207, 7.7% for 9, 12, 15, 16) and rearrangements (inversions, translocation markers were 56/207, 27.1%), which would have been missed. CONCLUSIONS: Use of current fluorescent in situ hybridization chromosome-specific probes protocols would have detected only 65% of chromosome abnormalities in our high-risk population. Incomplete ascertainment must be weighed against the cost and speed of fluorescent in situ hybridization chromosome-specific probes when comparing it with traditional karyotyping. Although this new technique may prove useful in low-risk screening programs (fetal cells in maternal blood), its current use in high-risk populations should be questioned until its sensitivity is expanded to identify more subtle and less common chromosomal abnormalities.

    Title Obstetric and Gynecologic Dysfunction in the Ehlers-danlos Syndrome.
    Date August 1994
    Journal The Journal of Reproductive Medicine
    Excerpt

    Women members of the newly formed Ehlers-Danlos National Foundation (EDNF) were surveyed with a very detailed questionnaire with 50 questions concerning family history and inheritance, past medical history, and obstetric and gynecologic problems. They entailed the largest extant database on Ehlers-Danlos Syndrome (EDS) patients. The mean age of the 68 women who responded to the survey was 42 years; most had EDS types I, III, IV and unknown. Forty-three women had 138 pregnancies; 13 women never married. The stillbirth rate was 3.15% (3/95); the preterm delivery rate was 23.1% (22/95), and the spontaneous abortion rate was 28.9% (40/138). There was a cesarean delivery rate of 8.4%, with 14.7% having perinatal bleeding problems. One woman (EDS type IV) had congestive heart failure. Common gynecologic problems were recurrent anovulation (41.3%), recurrent vaginal infections (53%), abnormal cytologic smears (19%), sexual dysfunction (61%), irregular menses (28%), endometriosis (15.8%), vaginal dryness (25%) and a need for hysterectomy (19.1%). In this largest series of pregnancies with EDS, we found relatively high rates of abortion, preterm delivery, pregnancy-related bleeding and stillbirth. Women with EDS also seem to have high frequency of anovulation, vaginal infections, abnormal cytologic smears and dyspareunia.

    Title In Utero Surgical Treatment of Fetal Obstructive Uropathy: a New Comprehensive Approach to Identify Appropriate Candidates for Vesicoamniotic Shunt Therapy.
    Date July 1994
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVES: We present a new approach to prenatal evaluation and prediction of renal function and long-term outcomes for fetuses considered candidates for in utero surgery. STUDY DESIGN: A review of 34 cases of obstructive uropathies was made, with analysis of our approach to prenatal evaluation, the predictive value of urinary electrolytes and protein analysis in identifying renal dysplasia, and the outcomes of cases with and without in utero surgical intervention. RESULTS: Ten of 11 pregnancies that were terminated had dysplasia; one female had cloacal dysgenesis. In three of eight unshunted cases megacystis resolved after vesicocentesis. Eight of 15 shunted fetuses survived. Of those predicted to have good postnatal outcome, six of six demonstrated good postnatal renal function. Of those predicted to have poor outcomes, two of two had poor postnatal renal function and dysplasia. Seven of 15 shunted fetuses died, four of four predicted to have dysplasia were confirmed, and three died of nonrenal causes. CONCLUSIONS: Our prenatal approach successfully differentiated fetuses with underlying renal dysplasia from those without irreversible damage who subsequently benefited from in utero vesicoamniotic shunt placement.

    Title Sonographic Screening for Trisomy 21: Fetal Humerus:foot Length Ratio, a Useful New Marker.
    Date June 1994
    Journal Fetal Diagnosis and Therapy
    Excerpt

    We have analyzed morphometric measurements from midgestational fetal necropsies and shown that arm and foot lengths are linear relationships versus gestational age (GA). Using foot length as the GA determinant, we found that the ratio of arm:foot length was also a linear relationship and was decreased in trisomy 21 fetuses when compared to age-matched normals. Based on these laboratory findings, we prospectively evaluated the use of the humerus:foot length ratio as a sonographic screening tool for identification of fetuses at risk for trisomy 21. Humerus length, foot length and the humerus:foot length ratio were found to be linear relationships vs. gestational age in both the normal and trisomy 21 populations. However, the regressions for the humerus:foot length ratio were significantly different between normals and Down's fetuses (p < 0.001). We found that a humerus:foot length ratio < or = 0.85 correctly identified 47% of our trisomy 21 fetuses (spec = 0.92, PPV = 0.25, NPV = 0.97). When compared to women > or = 35 years old in our high risk population, a humerus:foot length ratio < or = 0.85 carried an odds ratio of 52.7 (99% CL = 9.72-285.23) for trisomy 21.

    Title Fetal Therapy--1994.
    Date June 1994
    Journal Current Opinion in Obstetrics & Gynecology
    Excerpt

    Treatment of fetal anomalies has allowed the intact survival of increasing numbers of fetuses with previously fatal or very likely fatal disorders. Percutaneous in-utero surgery for obstructed bladders and thoracic effusions, and open surgery for diaphragmatic hernias and lung malformations has become increasingly successful. Medical and gene therapy approaches are likewise expanding and will continue to become more available.

    Title Birth Weight-length Ratios, Ponderal Indexes, Placental Weights, and Birth Weight-placenta Ratios in a Large Population.
    Date June 1994
    Journal Archives of Pediatrics & Adolescent Medicine
    Excerpt

    BACKGROUND: Birth weight (BW)/length ratios, ponderal indexes, placental weights, and BW/placental weight ratios have been correlated with perinatal morbidity and mortality. METHODS: Cross-sectional survey of live-born, structurally normal, singleton neonates delivered at a tertiary care center in Detroit, Mich, from 1984 through 1991. Subjects were included if dating based on menstrual dates and ultrasonographic estimations agreed with Ballard examination to within 2 weeks. RESULTS: Of 33,138 neonates, 26,983 (81.4%) were black. While all indexes significantly increased with advancing gestational age, only placental weights (without prior draining of blood, blotting the placenta dry, or trimming the membranes or cord) and BW/length ratios significantly increased beyond 40 weeks' gestation. Multivariate analysis of variance revealed that placental weights, BW/placenta ratios, and BW/length ratios were significantly related to gender and ethnicity, but ponderal index was not. Placental weights were larger, and BW/placenta ratios were smaller than studies that trimmed the placentas before weighing. CONCLUSIONS: All indexes were gestational age dependent, but ponderal index and BW/placenta ratios do not increase beyond 40 weeks' gestation. Except for ponderal index, interpretation of these indexes should be specific for ethnicity, gender, and manner of placental preparation.

    Title Technical Aspects of Transcervical Chorionic Villus Sampling.
    Date May 1994
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Following the 1990 FDA approval of the Trophocan catheter for use in transcervical chorionic villus sampling (CVS), an increasing number of US physicians have begun offering the procedure. To obtain privileges to perform CVS, some states such as California have enacted legislation requiring the performance of a certain number of CVS procedures in pregnancies in which the patient has already chosen first-trimester abortion. This practice is not universally feasible for legal, logistic, or financial reasons. We describe our approach to training in a busy reproductive genetics service. The physician initially trains by performing amniocentesis to optimize skills in ultrasound-directed needle guidance and placement. During this initial period, he or she also assists in performing transabdominal CVS procedures. The initial transcervical CVS cases should be performed in those situations requiring minimal catheter manipulation, or in those individuals undergoing CVS in the setting of spontaneous abortion. Cases of increasing difficulty should only be performed as skill and familiarity increase. For a physician already skilled and experienced in ultrasound-guided invasive procedures, sequential periods of observation at a busy center allows him or her to become familiar with the common pitfalls in performing transcervical CVS, and thus avoid them. Using this approach, we have performed over 5,000 CVS procedures and trained 6 reproductive genetics fellows in transcervical CVS.

    Title Prenatal Diagnosis of Congenital Megalourethra.
    Date March 1994
    Journal Journal of Ultrasound in Medicine : Official Journal of the American Institute of Ultrasound in Medicine
    Title Maternal Serum Alpha-fetoprotein Screening: the Need to Use Race/ethnic Specific Medians in Asians.
    Date February 1994
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVES. We questioned whether race-specific databases for maternal serum alpha-fetoprotein (MSAFP) screening should be added to those already available for African-American and white patients. STUDY DESIGN. We analyzed 138,272 MSAFP samples. The geographic origin of the samples was New York metropolitan area. Patients were classified as white, African-American, Hispanic or Asian. The usual adjustments were made and groups compared. Statistical analysis included ANOVA and multiple comparison test. RESULTS. MSAFP values are highest (p < 0.05) for Asians, followed by African-Americans, Hispanics, and whites, although the difference between Hispanic and white was not significant. CONCLUSIONS. Four separate databases are definable if specimen quantity is sufficient. Race/ethnic specific databases are more likely to yield the most accurate detection of abnormal MSAFP values, and therefore, fetal anomalies.

    Title Meroanencephaly: Pathology and Prenatal Diagnosis.
    Date February 1994
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Meroanencephaly is a rare form of anencephaly characterized by malformed cranial bones and a median cranial defect, through which protrudes abnormal tissue, called the area cerebrovasculosa. Area cerebrovasculosa denotes abnormal spongy, vascular tissue admixed with glial tissue ranging from a thin membrane to a large pseudoencephalic mass simulating cerebral tissue, that is composed of connective tissue, hemorrhagic vascular channels, glial nodules, and disorganized choroid plexuses. There are three types of anencephaly: (1) meroanencephaly, where there is rudimentary brain tissue and partial formation of the cranium; (2) holoanencephaly, the most common type, in which the brain is completely absent, and (3) craniorachischisis, the most severe, where area cerebrovasculosa and area medullovasculosa fill both cranial defects and the spinal column. In meroanencephaly, there is a median defect present, through which protrudes the area cerebrovasculosa. We present 3 cases of meroanencephaly diagnosed prenatally, along with histopathologic analysis. One case showed ectopic glial tissue in the lung and adrenal medullary hyperplasia. Two cases were diagnosed in the early second trimester by ultrasound scanning. Meroanencephaly may be mistaken for encephalocele both at the bedside exam and sonographically, and should be included in the differential for protruding anterior cranial masses.

    Title Prenatal Diagnosis of Congenital Diaphragmatic Hernia Not Amenable to Prenatal or Neonatal Repair: Brachmann-de Lange Syndrome.
    Date February 1994
    Journal American Journal of Medical Genetics
    Excerpt

    Brachmann-de Lange syndrome (BDLS) is a variable multiple congenital anomaly syndrome that occasionally includes congenital diaphragmatic hernia (CDH). CDH per se is commonly diagnosed antenatally and has been corrected with increasing success in utero and by neonatal repair with extracorporeal membrane oxygenation (ECMO). In utero repair requires normal karyotype as well as the absence of other lethal anomalies. Postnatal repair in combination with ECMO has resulted in improved neonatal outcome and has been recommended in all cases not having in utero repair. We describe a fetus diagnosed with a diaphragmatic hernia at 18 weeks of gestation in a woman whose only other pregnancy has been a 16 week abortus diagnosed with Fryns syndrome (FS). FS is a lethal, variable congenital anomaly syndrome that includes CDH, which is thought to contribute to the lethality of the syndrome. In utero repair was considered, but rejected because of the position of the liver and suspected FS. The patient elected to carry the pregnancy to term. Postnatal repair with ECMO was considered; however, the infant died at several hours of age because of severe pulmonary hypoplasia, being considered ineligible for ECMO. The diagnosis of BDLS was made at autopsy and suggests that the first case may, in fact, have been BDLS. In spite of recent success in the repair of CDH both in et ex utero, CDH in association with BDLS is likely lethal, and women with fetuses diagnosed antenatally with CDH and BDLS should be counseled as such.

    Title Maternal Neurosurgical Shunts and Pregnancy Outcome.
    Date January 1994
    Journal Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: To assess pregnancy outcome in women with ventriculoperitoneal or lumboperitoneal shunts. METHODS: Charts were reviewed retrospectively for mothers with ventriculoperitoneal or lumboperitoneal shunts delivered at Hutzel Hospital from 1976-1992. Patients were identified by cross-referencing medical records from Children's Hospital Neurosurgical Division and medical records at Hutzel Hospital during this period. RESULTS: Eight patients with 25 pregnancies were identified from 1976-1992. Indications for shunt placement were pseudotumor cerebri (four with lumboperitoneal shunts) and congenital hydrocephalus (four with ventriculoperitoneal shunts). Pregnancy outcomes were two elective abortions, five spontaneous abortions, two preterm vaginal deliveries, one mid-forceps rotation, two primary low transverse cesareans, two repeat low transverse cesareans, and 11 spontaneous vaginal deliveries. No patient received prophylactic antibiotics during labor and vaginal delivery because of the shunt. There were no shunt-related complications. CONCLUSIONS: This series doubles the number of previously reported pregnancy outcomes in women with neurosurgical shunts. Contrary to the literature suggesting cesarean delivery and prophylactic antibiotics for all patients, our experience suggests that vaginal delivery can be considered and that prophylactic antibiotics are not an absolute necessity in uncomplicated vaginal deliveries.

    Title Amniotic Fluid Platelet Factor 4 and Beta-thromboglobulin As Markers of Structural Abnormalities.
    Date December 1993
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Platelet factor 4 (PF4) and beta-thromboglobulin (BTG) are unique markers of irreversible platelet activation. We measured PF4 and BTG in amniotic fluid from 102 genetic amniocenteses, in which 78 had normal amniotic fluid alpha-fetoprotein (AFP) levels with normal pregnancies, and 24 had high amniotic fluid AFP levels with abnormal pregnancies. PF4 and BTG were significantly higher in the abnormal pregnancy/elevated amniotic fluid AFP group (p < 0.002 in each case) and correlated with AFP expressed as multiples of the median (p < 0.05 and p < 0.0001, respectively). Our results are compatible with passage of PF4 and BTG across fetal membranes and/or enhanced fetal platelet activation in fetuses with structural anomalies and elevated AFP.

    Title Amniotic Fluid Platelet Factor 4 and Beta-thromboglobulin.
    Date December 1993
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Platelet activating factor (PAF), a powerful platelet activator, has been identified in human embryos and fetuses, and may induce fetal lung maturation. The potential effect of PAF on fetal platelets as indicated by release of beta-thromboglobulin (BTG) and platelet factor 4 (PF4) has not been investigated. We measured BTG and PF4 in amniotic fluid from 78 genetic and 35 pulmonary maturity amniocenteses. BTG and PF4 were higher in the genetic amniocentesis samples (p < 0.001 in each case) than in the lung maturity samples. BTG and PF4 did not correlate with the pulmonary maturity parameters as measured by the lecithin to sphingomyelin ratio and phosphatidylglycerol concentration. Our findings suggest a fetal origin of BTG and PF4 in amniotic fluid.

    Title Amniotic Fluid Acetylcholinesterase is Found in Gastroschisis but Not Omphalocele.
    Date December 1993
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Amniotic fluid acetylcholinesterase (ACHE) has been used to evaluate neutral tube defects. It has also been detected in ventral wall defects. However, the role of ACHE to differentiate between omphalocele and gastroschisis has not been established. We examined amniotic fluid ACHE in 16 pregnancies complicated by gastroschisis and 8 by omphalocele. One ruptured omphalocele was excluded. ACHE was negative in all 7 omphaloceles and either positive or suspicious in all gastroschises (chi 2 = 17.3, p < 0.0001). Amniotic fluid ACHE may be useful to differentiate between omphalocele and gastroschisis.

    Title Immediate Delivery Room Repair of Fetal Abdominal Wall Defects.
    Date December 1993
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Eighteen patients with a prenatal diagnosis of fetal abdominal wall defect were delivered by cesarean section and repaired either immediately (begun within 15 min, n = 9), or by the traditional (delayed) method (n = 9, average delay = 4.4 h). Neonates repaired immediately had comparable gestational ages and birthweight, however, subjectively had less edematous bowel with less fibrous peel. These fetuses were more likely to be closed primarily (7/9 vs. 4/9), spent less time on a ventilator (8.1 vs. 17.9 days), seemed to be fed sooner (7.6 vs. 17.9 days), and discharged home earlier (14.3 vs. 24.0 days). Our results suggest that for fetuses delivered by cesarean section, early defect repair may reduce bowel edema and fibrous peel formation thus facilitating primary closure, with earlier ventilator weaning, feeding and discharge home.

    Title Tuberculosis and Hiv Disease.
    Date December 1993
    Journal Aids Clinical Review
    Title Fetal Drug Therapy.
    Date December 1993
    Journal The Western Journal of Medicine
    Excerpt

    Fetal drug therapy encompasses several areas, including the prevention of external genital masculinization in 21-hydroxylase deficiency syndrome (congenital adrenal hyperplasia), biochemical amelioration of methylmalonic acidemia, and biotin-responsive multiple carboxylase deficiency. The correction of cardiac arrhythmias has become relatively commonplace, and a reduction in the risks of neural tube defects is now possible with the use of preconceptual and early conceptual folic acid. Similarly, fetal function can be altered by the induction of fetal lung maturity using a number of agents; corticosteroids are the most common fetal pharmaceutic agent, and a number of other agents have also been tried. The most common route of administering pharmaceutic agents is through the mother and the placenta, although the direct administration of certain agents is becoming more common.

    Title Prenatal Diagnosis: Choices Women Make About Pursuing Testing and Acting on Abnormal Results.
    Date November 1993
    Journal Clinical Obstetrics and Gynecology
    Title Fetal Leg and Femur/foot Length Ratio: a Marker for Trisomy 21.
    Date October 1993
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Our purpose was to determine whether the femur/foot length ratio is useful in the prenatal detection of trisomy 21. STUDY DESIGN: Direct necropsy measurements were analyzed on 436 midgestational fetuses (391 normal, 45 with trisomy 21). Necropsy leg/foot length ratio versus gestational age was found to be significantly different between normal fetuses and those with trisomy 21. On the basis of the necropsy data, 345 midgestational pregnancies were evaluated ultrasonographically for femur/foot length ratio versus gestation age to identify fetuses at risk for trisomy 21. RESULTS: A leg/foot length ratio versus gestation age < or = 2.3 correctly identified 84% of fetuses with trisomy 21 between 110 to 155 days gestation age at necropsy. An ultrasonographic femur/foot length ratio versus gestational age < or = 0.9 had an 18.3 odds ratio risk for trisomy 21 in our high-risk population and correctly identified 71% of fetuses with trisomy 21 (positive predictive value 0.24, negative predictive value 0.98). CONCLUSION: The femur/foot length ratio is an additional ultrasonographic marker for identification of fetuses at increased risk for trisomy 21.

    Title Doi and Alpha-methylserotonin: Comparative Vascular and Nonvascular Smooth Muscle Effects and Central 5-hydroxytryptamine2 Receptor Affinities.
    Date September 1993
    Journal The Journal of Pharmacology and Experimental Therapeutics
    Excerpt

    Both alpha-methylserotonin and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) are agonists at 5-hydroxytryptamine2 (5-HT2) receptors. The present study compared these agonists for their binding affinities at the high- and low-affinity states of the 5-HT2 receptor and for their contractile activities in certain smooth muscle preparations. Both agonists contracted the rat aorta and rat jugular vein, tissues possessing 5-HT2 receptors, and contraction was blocked by ketanserin. However, alpha-methylserotonin produced greater maximal response (80-90% maximum response to serotonin) than DOI. In the rat jugular vein, the calculated dissociation constant of DOI (-log Kb = 7.7) corresponded well with its affinity for [3H]ketanserin- (pKi = 7.5) but not [125I]DOI- (pKi = 8.6) radiolabeled sites. This might suggest that binding to the agonist low-affinity state of the 5-HT2 receptor is more relevant to vascular agonist activity. alpha-Methylserotonin was slightly more potent than serotonin in contracting the rat aorta but not the jugular vein, whereas DOI was more potent in the jugular vein than in the aorta. In the jugular vein but not the aorta, the relative potency of these agents corresponded well with their relative affinities for either the [3H]ketanserin- or the [125I]DOI-labeled 5-HT2 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Viable Pregnancies After Diagnosis of Trisomy 16 by Cvs: Lethal Aneuploidy Compartmentalized to the Trophoblast.
    Date August 1993
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Increasing utilization of chorionic villus sampling (CVS) has lead to the discovery that the placenta can karyotypically be a very heterogeneous organ, and chromosomal mosaicism within the placental can confuse cytogenetic interpretation. Recently, confined placental mosaicism (confined regions of aneuploidy in the otherwise normal diploid placental and fetus) has been described involving a number of chromosomal abnormalities. Fetal trisomy 16 is considered uniformly lethal early in gestation. However, we present 3 cases of nonmosaic trisomy 16 confined regionally to the placenta. We discuss the possible etiology, impact on the developing fetus, and suggest an approach to the workup and evaluation of cases where the karyotype obtained on CVS is not compatible with the findings on ultrasound.

    Title Two Consecutive Hydrolethalus Syndrome-affected Pregnancies in a Nonconsanguinous Black Couple: Discussion of Problems in Prenatal Differential Diagnosis of Midline Malformation Syndromes.
    Date July 1993
    Journal American Journal of Medical Genetics
    Excerpt

    Hydrolethalus syndrome is a rare autosomal recessive (AR) disorder characterized by polyhydramnios, CNS abnormalities, cleft lip/palate, micrognathia, and polydactyly. Its molecular basis is unknown and prenatal diagnosis is challenging due to phenotypic overlap with several other midline malformation syndromes. A 34-year-old G3P2, nonconsanguinous, married, African-American woman was referred at 19 weeks of gestation after ultrasound findings of "multiple congenital anomalies." A previous pregnancy had been terminated following ultrasound findings of polyhydramnios, cleft lip/palate, polydactyly, severe hydrocephalus, and a Dandy-Walker malformation (DWM). Level II ultrasound evaluation of the current pregnancy demonstrated all of the anomalies which had been present in her previous pregnancy. Karyotype of amniocytes was 46,XX. Autopsy following pregnancy termination confirmed ultrasound findings. The pedigree, sonographic, and autopsy findings in this case were most consistent with hydrolethalus syndrome, although other AR multiple midline malformation syndromes were considered. Our case was detected by 19 weeks. Confident differential diagnosis is difficult for the geneticist and even more so for the sonologist given the technical limitations of ultrasound. It is uncertain whether these mendelian midline malformation syndromes represent slightly different phenotypic expressions of a common genetic defect or are manifestations of allelic and or locus heterogeneity. We suggest that for prenatal diagnostic purposes, in the absence of knowledge of the molecular basis of these disorders, the fine distinctions are not crucial as long as their mendelian inheritance is recognized and presence or absence of manifestations which make them severe are ascertained.

    Title Efficacy of Transabdominal Multifetal Pregnancy Reduction: Collaborative Experience Among the World's Largest Centers.
    Date July 1993
    Journal Obstetrics and Gynecology
    Excerpt

    To evaluate the safety and efficacy of transabdominal multifetal pregnancy reduction (MFPR) in the management of iatrogenic and spontaneous multifetal pregnancies.

    Title The Choices Women Make About Prenatal Diagnosis.
    Date July 1993
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Despite the rapid advancement and increasing utilization of prenatal diagnostic technologies, there has been a paucity of investigation into the psychological, socioeconomic, and demographic features associated with the choices women make about both the uptake of services, and the actions taken after fetal abnormalities are discovered. From 1986 through 1991 we have completed four studies initiating a proposed comprehensive evaluation of these factors. The first two studies concentrated on patient features influencing uptake of prenatal diagnostic procedures in both a priori 'high risk' pregnancies (advanced maternal age) as well as in previously 'low risk' pregnancies which had become 'high risk' by virtue of abnormal maternal alpha-fetoprotein (MSAFP) screening. The second two studies evaluated features influencing abortion decisions after the discovery of either chromosomal anomalies, or non-aneuploid ultrasonographically detected structural abnormalities. Data suggested that (1) older and more highly educated women tended to choose CVS over amniocentesis; (2) perceptions of genetic risk within couples was most influenced by attributes of their partners; (3) anxiety and perception of risk was higher in young women having abnormal screening MSAFP, than in the advanced maternal age group although this difference appeared to be commensurate with actual risks; (4) for fetal aneuploidy, the specific karyotype and, to a lesser extent, coexistent structural anomalies are the major determinants of decisions to abort; (5) for euploid fetal structural abnormalities the prognostic severity and potential for beneficial medical intervention (either antenatally or postnatally) as counselled by the physician were the principal determinants influencing abortion decisions. Further study is needed and important questions still to be addressed are discussed.

    Title Skeletal Histopathology in Fetuses with Chondroectodermal Dysplasia (ellis-van Creveld Syndrome).
    Date May 1993
    Journal American Journal of Medical Genetics
    Excerpt

    Chondroectodermal dysplasia (CED) is an uncommon autosomal recessive disorder and one of the short rib polydactyly syndromes (SRPS). It is characterized by acromelic and mesomelic shortness of limbs, postaxial polydactyly, small chest, ectodermal dysplasia, and in many cases, congenital heart defects. Controversy exists over possible changes in the growth plate. With the advent of ultrasonographic examination, increasing numbers of fetuses with osteochondrodysplasias are examined by pathologists. Since histopathologic examination of the skeletal system is useful in defining various osteochondrodysplasias and it has not been described in the fetus with CED, we herein describe 3 cases of fetal CED with emphasis on skeletal histopathology. All 3 pregnancies were terminated at 22-23 weeks because of ultrasonographic demonstration of short limbs and growth retardation. Radiologically, each fetus had acromelic and mesomelic shortness of long bones with smooth round metaphyses, vertically short iliac bones, short ribs and normal vertebrae. These findings are similar to those described in the larger newborn infant with CED. Histopathologically, the cartilage of the long bones showed chondrocytic disorganization in the physeal growth zone. The findings are dissimilar to those of larger infants and older children in whom chondrocytic columnization has been seen in the central physis and disorganization in peripheral physis. Furthermore, a variable degree of chondrocytic disorganization was also seen in the central physeal growth zone of vertebrae in these fetuses. Other findings noted at fetopsy were: polydactyly in all 3 cases, congenital heart defect in 2 and an abnormal frenulum in one case. The foregoing phenotypic and radiographic manifestations and skeletal histopathology help separate CED from other SRPS.

    Title Uniparental Disomy for Chromosome 16 in Humans.
    Date March 1993
    Journal American Journal of Human Genetics
    Excerpt

    The association between chromosomal mosaicism observed on chorionic villus sampling (CVS) and poor pregnancy outcome has been well documented. CVS mosaicism usually represents abnormal cell lines confined to the placenta and often involves chromosomal trisomy. Such confined placental mosaicism (CPM) may occur when there is complete dichotomy between a trisomic karyotype in the placenta and a normal diploid fetus or when both diploid and trisomic components are present within the placenta. Gestations involving pure or significant trisomy in placental lineages associated with a diploid fetal karyotype probably result from a trisomic zygote which has lost one copy of the trisomic chromosome in the embryonic progenitor cells during cleavage. Uniparental disomy would be expected to occur in one-third of such cases. Trisomy of chromosome 7, 9, 15, or 16 is most common among the gestations with these dichotomic CPMs. Nine pregnancies with trisomy 16 confined to the placenta were prenatally diagnosed. Pregnancy outcome, levels of trisomic cells in term placentas, and fetal uniparental disomy were studied. Intrauterine growth retardation (IUGR), low birthweight, or fetal death was observed in six of these pregnancies and correlated with high levels of trisomic cells in the term placentas. Four of the five cases of IUGR or fetal death showed fetal uniparental disomy for chromosome 16. One of the infants with maternal uniparental disomy 16 had a significant malformation (imperforate anus). All infants with normal intrauterine growth showed term placentas with low levels of trisomic cells.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Triply Discordant Triplets: Probability, Management Options, and Risks.
    Date February 1993
    Journal American Journal of Medical Genetics
    Excerpt

    The spontaneous occurrence of triplets is rare. With increased utilization of "assisted reproductive technologies," multifetal gestations have become more common. The empiric fetal risk for major malformation is approximately 3%. In a triplet pregnancy each fetus independently carries this risk so that the probability of having at least one malformed fetus is approximately 9%. It is much less likely to have 2 or 3 simultaneously but discordantly malformed fetuses in a multizygotic triplet gestation (.09% and .0027% risk, respectively). We report on the first case, to our knowledge, of an ovulation-stimulated triplet pregnancy complicated by 3-way discordance for major malformations diagnosed in the late second trimester by ultrasound. Fetus A was affected by congenital diaphragmatic hernia and trisomy 21; fetus B had encephalocele, a midline facial defect, and a cleft palate; and fetus C had evidence of unilateral claw hand but an otherwise normal fetal survey. At 19 weeks of gestation, fetus A was found to have spontaneously died, and a selective termination of triplet B was performed. We conclude: (1) the finding of a single major malformation in one fetus should lead to extensive search for malformations in all members of the pregnancy, and (2) the simultaneous occurrence of major malformations in more than one member of a multifetal gestation is a circumstance under which multiple selective termination deserves consideration. In this article we discuss important issues and caveats in the performance of selective termination for abnormal members of multifetal gestations.

    Title Tetraploidy Associated with Human Pronuclear Embryo Cryopreservation: a Case Report.
    Date February 1993
    Journal Journal of Assisted Reproduction and Genetics
    Title First-trimester Simple Hygroma: Cause and Outcome.
    Date February 1993
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: First-trimester fetuses with simple nuchal hygromas represent a population that is different from midgestation nuchal cystic hygroma in terms of karyotype abnormalities and long-term prognosis. STUDY DESIGN: Sixty-eight consecutive fetuses diagnosed with simple nuchal hygromas between 10 and 14 weeks' gestation were evaluated ultrasonographically and karyotyped. Those with normal chromosome complements were ultrasonographically monitored throughout the remainder of the pregnancy for resolution of their hygromas. RESULTS: Twenty-three of 27 fetuses with normal karyotypes resolved their hygromas within 4 weeks of diagnosis and were phenotypically normal at birth. Forty-one fetuses were karyotypically abnormal, with trisomy 21 being the most common abnormality. CONCLUSIONS: Fetuses with first-trimester simple nuchal hygromas are at high risk for aneuploidy and should be offered prenatal testing. Such fetuses with normal karyotypes will likely resolve their hygromas by 18 weeks' gestation, and most will be phenotypically normal at birth.

    Title The Smaller Than Expected First-trimester Fetus is at Increased Risk for Chromosome Anomalies.
    Date January 1993
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Intrauterine growth retardation associated with fetal chromosome anomalies is usually documented on ultrasonography late in the second trimester. However, we believe and attempt to document here that the impact of aneuploidy on fetal growth is evident much earlier (i.e., the aneuploid fetus may appear smaller than dates on ultrasonography even in the first trimester). STUDY DESIGN: For the population referred to our center for chorionic villus sampling from January 1988 to July 1991, we compared gestational age as calculated from the last menstrual period to that derived from fetal size as measured by crown-rump length. A cutoff of 7 days was chosen to select the study group. The remainder of our chorionic villus sampling population in which fetal size was expected was used as controls. We also divided those chorionic villus sampling patients by when a fetal death was observed by size. RESULTS: In the study period 3194 chorionic villus sampling procedures were performed and in 277 (8.7%) fetal length was smaller than expected by at least 7 days. Sixty (1.9%) chromosome anomalies were diagnosed by first trimester chorionic villus sampling in the study period. The frequency of chromosome anomalies was 4.3% in the study group and 1.7% in controls (p < 0.004). The more aberrant the karyotype on "postmortem chorionic villus sampling," the greater the growth retardation tended to be. CONCLUSIONS: In our chorionic villus sampling population a fetal crown-rump length smaller than dates is associated with a significant increase in risk of chromosome anomalies. Moreover, the larger the size-dates discrepancy, the higher the possibility that the aneuploidy affecting that pregnancy is of the severe or lethal type.

    Title First Trimester Interfetal Size Variation in Well-dated Multifetal Pregnancies.
    Date September 1992
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Sonographic measurements of multifetal pregnancy for dating and growth are considered identical to singleton pregnancies until the second trimester. Observations in 57 patients having triplets or more, who were referred for first trimester multifetal pregnancy reduction, suggest considerable size variability both within an individual pregnancy and among pregnancies of the same gestational ages (GAs). These data are unique because the GAs are precisely known, because the pregnancies were established by assisted reproductive technology. We observed a greater standard deviation at 12 and 13 weeks of GA. We also observed significant interfetal variation within an individual pregnancy. Because multifetal pregnancy reduction was performed, follow-up of any given fetus to term was not possible. We conclude that for high-order multiple gestations: (1) interfetal size variability begins much earlier than often stated; (2) differences in the degree of variability can be observed among different pregnancies of the same gestational age and within the same pregnancy, and (3) there is a trend for increasing variability with increasing gestational age.

    Title Chorionic Villus Sampling: Transabdominal Versus Transcervical Approach in More Than 4000 Cases.
    Date September 1992
    Journal Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: To address the evolving trends in the choice of transabdominal or transcervical chorionic villus sampling (CVS) at a teaching hospital and to evaluate the influence of gestational age on the approach chosen. METHODS: We analyzed our CVS data base, which contained information from 1986-1991. The proportions of transabdominal and transcervical CVS were tabulated for each year. In addition, the distribution of the CVS approaches over the various gestational ages was examined. RESULTS: During the study period, 4290 CVS procedures were performed. The rate of the transabdominal technique was stable at about 15% per year except for the first 2 years, when essentially all procedures were transcervical. Use of transabdominal CVS increased with advancing gestational age, from 3.6% at less than 10 weeks' gestation to 97.6% at greater than 14 weeks (chi 2 = 120, P less than .001; r = 0.791). CONCLUSIONS: The choice between the transabdominal and transcervical approach to CVS largely reflects the route emphasized during the physician's training. When choice is based strictly on technical limitations due to placental position, the overall transabdominal CVS rate is approximately 15%. A shift from transcervical to transabdominal CVS occurs with increasing gestational age as the placenta gains bulk and moves away from the cervix. After 14 weeks' gestation, most procedures are performed transabdominally.

    Title Fetal Intracardiac Potassium Chloride Injection to Avoid the Hopeless Resuscitation of an Abnormal Abortus: I. Clinical Issues.
    Date August 1992
    Journal Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: With the intention of preventing the attendant medical, ethical, and legal problems arising from the birth of live-born, anomalous fetuses, we initiated a program offering fetal intracardiac potassium chloride injection as an adjunctive measure in the setting of genetically indicated second-trimester abortion. METHODS: A lethal fetal injection was offered to patients carrying chromosomally or structurally abnormal fetuses at 19-24 weeks' gestation who desired abortion. When the patient elected this procedure, real-time ultrasound guidance was used to inject 3-5 mL of potassium chloride (2 mEq/mL) directly into the fetal cardiac chambers, followed by observation of fetal heart activity to ascertain cessation. Labor was subsequently induced with uterotonic prostaglandins. RESULTS: The procedure caused immediate cessation of fetal heart motion in 20 of 21 cases. There were no maternal complications. No fetuses were live-born. CONCLUSIONS: Direct fetal intracardiac potassium chloride injection effectively causes immediate fetal cardiac arrest. This approach may be adopted in cases of abortion by labor-induction methods at advanced gestations to ensure that the abortus is stillborn.

    Title Fetal Intracardiac Potassium Chloride Injection to Avoid the Hopeless Resuscitation of an Abnormal Abortus: Ii. Ethical Issues.
    Date August 1992
    Journal Obstetrics and Gynecology
    Excerpt

    Following the diagnosis of a genetic anomaly, some couples choose to have a legal abortion. However, following later abortions at greater than 20 weeks, the rare but catastrophic occurrence of live births can lead to fractious controversy over neonatal management. To avoid this situation, we have added fetal intracardiac potassium chloride injection to cause fetal cardiac arrest before induction of labor. The ethical issues surrounding such a practice are complex. We support this practice for three reasons: 1) The women's decision for abortion is protected because this practice assures her right for non-interference; 2) potential psychological harm to the patient and other family members is avoided; and 3) the potential for coercive intervention by other health care personnel is eliminated. At least three objections can be raised: 1) All abortions are unjust; 2) newborns and second-trimester fetuses at similar weights with identical defects should be managed in like fashion; and 3) the patient is not entitled to death of the fetus, only to evacuation of the uterine contents. On balance, we believe that our approach is justifiable ethically as it reduces the burden of conflict between the wishes of the patient and those of the neonatal care givers. It should be introduced only in situations in which the likelihood of civil or criminal liability or unwarranted medical intervention is high.

    Title Traditional and Molecular Cytogenetics.
    Date August 1992
    Journal The Journal of Reproductive Medicine
    Excerpt

    Traditional cytogenetic methods have relied on tissue culture techniques to generate adequate mitotic cells for the analysis of chromosome disorders for prenatal diagnosis. Chromosome banding techniques allow the evaluation of mitotic cells for structural and numerical aberrations and define the nature of any rearrangement. With the advent of fluorescent in situ hybridization methodology, which combines the molecular technologies of chromosome-specific probes and in situ molecular hybridization, it has become possible to analyze chromosomal numerical and structural aberrations from interphase cells. The use of molecular cytogenetic techniques should greatly increase the speed and diagnostic resolution of clinical specimens.

    Title Tuberculin Skin Test Reactivity Among Adults Infected with Human Immunodeficiency Virus.
    Date July 1992
    Journal The Journal of Infectious Diseases
    Excerpt

    Infection with the human immunodeficiency virus type 1 (HIV-1) results in decreased cell-mediated immunity, which includes decreased delayed hypersensitivity to skin test antigens. HIV-1 seropositivity and skin test reactivity to purified protein derivative (PPD) were determined among 2042 healthy Haitian adults with normal chest radiographs. Among HIV-1-seropositive individuals, 52.3% (146/279) had PPD reactions greater than or equal to 10 mm compared with 67.2% (1184/1763) of the seronegative adults (P less than .001). However, the percentage of HIV-1-seropositive individuals with PPD reactions greater than or equal to 5 mm was similar to the percentage of seronegative adults with PPD reactions greater than or equal to 10 mm (180/279 [64.5%] vs. 1184/1763 [67.2%]). Assuming that the rate of prior infection with Mycobacterium tuberculosis was similar for HIV-1-seronegative and -seropositive populations, these data provide support for the recent recommendations to use induration of greater than or equal to 5 mm as evidence of past infection with M. tuberculosis in HIV-1 seropositive adults.

    Title Determinants of Parental Decision to Abort or Continue After Non-aneuploid Ultrasound-detected Fetal Abnormalities.
    Date July 1992
    Journal Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: This study evaluated factors influencing the decision to abort after abnormalities in the karyotypically normal fetus were found through ultrasonography. METHODS: We reviewed all pregnancies complicated by ultrasound-detected abnormalities managed on our service from April 1990 through August 1991 (N = 262). Cases with associated karyotypic abnormalities were excluded (N = 35), as were cases diagnosed after the legal gestational age limit for abortion (N = 68). The remaining 159 cases were stratified into prognosis groups of "severe," "uncertain," and "mild." RESULTS: The prognostic severity of the ultrasound abnormality strongly correlated with the decision to abort (P less than .0001). Rates of termination were 0, 12, and 66% in the "mild," "uncertain," and "severe" groups, respectively. The patients' age, gravidity, and parity, and the fetal gestational age at diagnosis did not differ significantly between the groups. CONCLUSIONS: 1) In non-aneuploid pregnancies with an ultrasound diagnosis of fetal abnormality, the major predictor of the decision to abort was the severity of fetal prognosis. 2) The gestational age at diagnosis was not an important variable in the decision to abort for fetal structural abnormalities. 3) Parents who had fetuses with abnormalities associated with uncertain prognoses usually opted to continue the pregnancy. This appeared to be particularly true for defects that were potentially correctable in utero or by neonatal intervention (even if investigational).

    Title In Utero Diagnosis of Congenital Varicella Zoster Virus Infection by Chorionic Villus Sampling and Polymerase Chain Reaction.
    Date January 1992
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Varicella zoster virus infection acquired in pregnancy is reported to cause fetal damage in 5% to 10% of cases. We used polymerase chain reaction to attempt molecular diagnosis of fetoplacental varicella zoster virus infection in two patients. Tissue obtained by chorionic villus sampling in the second trimester was analyzed by polymerase chain reaction with a varicella zoster virus-specific primer, ORF-63, and was found to be positive in both patients. Viral cultures were negative. One patient elected pregnancy termination at 23 weeks. Southern blot hybridization of neonatal brain tissue for varicella zoster virus was negative. The second patient carried the pregnancy to term and was delivered of a normal infant. Varicella zoster virus immunoglobulin M and viral cultures were negative. The presence of viral deoxyribonucleic acid sequences in placental tissue does not correlate with fetal disease.

    Title Vaginal Laceration Following a Jet-ski Accident.
    Date November 1991
    Journal Obstetrics and Gynecology
    Excerpt

    A 17-year-old woman riding as a passenger on a jet-ski fell behind the jet nozzle while jumping waves. A vaginal laceration with intra-abdominal extension occurred as a result of the accident. Hypogastric artery ligation controlled the hemorrhage and avoided more extensive surgery. The case represents an unusual injury from this type of watercraft and illustrates important points in the management of genital tract trauma.

    Title Amphetamine Derivatives Induce Locomotor Hyperactivity by Acting As Indirect Serotonin Agonists.
    Date November 1991
    Journal Psychopharmacology
    Excerpt

    Derivatives of amphetamine are potent releasers of both dopamine (DA) and serotonin (5-HT), but the relative contributions of DA and 5-HT release to the behavioral effects of these drugs have not been established. Previously, S-(+)3,4-methylenedioxymethamphetamine (S-(+)MDMA) was found to produce locomotor hyperactivity in rats which was dependent on 5-HT release. The present study found that MBDB (1.25, 2.5, 5.0 or 10.0 mg/kg), the alpha-ethyl derivative of MDMA that produces little or no direct DA release, also induced locomotor hyperactivity that lasted for greater than 60 min after the 5.0 and 10.0 mg/kg doses. MBDB produced spatial patterns of locomotor hyperactivity and suppression of exploratory activity (holepokes and rearings) very similar to the behavioral syndrome produced by MDMA. MBDB-induced hyperactivity was blocked by pretreatment with the selective 5-HT uptake inhibitor fluoxetine (2.5 or 10 mg/kg), suggesting that MBDB produced behavioral effects via uptake-carrier mediated release of 5-HT. Similarly, fluoxetine pretreatment blocked the locomotor hyperactivity produced by S-(+)3,4-methylenedioxyamphetamine (3.0 mg/kg) or p-chloroamphetamine (2.5 mg/kg), supporting a serotonergic basis for the action of these drugs. Tissue levels of 5-HT and its metabolite 5-HIAA were decreased 40 min after administration of S-(+)MDMA (3.0 mg/kg) or MBDB (5.0 mg/kg), and these decreases were prevented by fluoxetine pretreatment. S-(+)MDMA also produced a fluoxetine-sensitive increase of tissue DA levels, suggesting that 5-HT release may indirectly result in increased DA release, although MBDB did not significantly increase DA levels.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Enterobacter Bacteremia: Clinical Features and Emergence of Antibiotic Resistance During Therapy.
    Date October 1991
    Journal Annals of Internal Medicine
    Excerpt

    OBJECTIVES: To study the effect of previously administered antibiotics on the antibiotic susceptibility profile of Enterobacter, the factors affecting mortality, and the emergence of antibiotic resistance during therapy for Enterobacter bacteremia. DESIGN: Prospective, observational study of consecutive patients with Enterobacter bacteremia. SETTING: Three university tertiary care centers, one major university-affiliated hospital, and two university-affiliated Veterans Affairs medical centers. PATIENTS: A total of 129 adult patients were studied. MEASUREMENTS: The two main end points were emergence of resistance during antibiotic therapy and death. MAIN RESULTS: Previous administration of third-generation cephalosporins was more likely to be associated with multiresistant Enterobacter isolates in an initial, positive blood culture (22 of 32, 69%) than was administration of antibiotics that did not include a third-generation cephalosporin (14 of 71, 20%; P less than 0.001). Isolation of multiresistant Enterobacter sp. in the initial blood culture was associated with a higher mortality rate (12 of 37, 32%) than was isolation of a more sensitive Enterobacter sp. (14 of 92, 15%; P = 0.03). Emergence of resistance to third-generation cephalosporin therapy (6 of 31, 19%) occurred more often than did emergence of resistance to aminoglycoside (1 of 89, 0.01%; P = 0.001) or other beta-lactam (0 of 50; P = 0.002) therapy. CONCLUSIONS: More judicious use of third-generation cephalosporins may decrease the incidence of nosocomial multiresistant Enterobacter spp., which in turn may result in a lower mortality for Enterobacter bacteremia. When Enterobacter organisms are isolated from blood, it may be prudent to avoid third-generation cephalosporin therapy regardless of in-vitro susceptibility.

    Title In Utero Fetal Muscle Biopsy for the Diagnosis of Duchenne Muscular Dystrophy.
    Date October 1991
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Deoxyribonucleic acid techniques can be used to diagnose Duchenne muscular dystrophy prenatally in male fetuses that are at risk. Deoxyribonucleic acid-based prenatal diagnosis can be impossible when there is only one prior affected male and there is no identifiable deletion or alteration. We performed fetal muscle biopsy in utero in such a case and documented the presence of dystrophin, thereby confirming normality in a male fetus at risk. This first in utero experience adds fetal muscle biopsy to the available procedures for fetal tissue diagnosis.

    Title Postmortem Chorionic Villus Sampling: Correlation of Cytogenetic and Ultrasound Findings.
    Date September 1991
    Journal American Journal of Medical Genetics
    Excerpt

    We performed chorionic villus samplings (CVS) in 795 cases in the first trimester during a 13-month period. Of these 35 were found to have a blighted ovum or missed abortion prior to the procedure. Nineteen women consented to have CVS. Ultrasonographic and cytogenetic findings in these 19 pregnancies were correlated. Expected gestational age was determined by last menstrual period. Observed gestational age was determined by crown rump length (CRL) (12 pregnancies) or gestational sac (GS) (7 pregnancies without fetal pole). The differences in days between the estimated and observed gestational ages was determined for each pregnancy. In all 19 CVS samples cytogenetic diagnosis documented aneuploidy. Ten cases had chromosome abnormalities virtually always lethal in the embryonic period (group I). Nine pregnancies had defects with moderate potential for fetal viability (group II). Gestations with low viability potential (group I) had estimated minus observed gestational age discrepancies (23.4 +/- 8.3 days) significantly greater than gestations with moderate viability potential (group II) (8.9 +/- 4.3 days) (P less than .001). The absence of a fetal pole was more common in group I. CVS in pregnancies with missed abortion or blighted ovum is feasible and has a high likelihood of documenting aneuploidy. Furthermore, the more severe the anomaly the more likely there will be very early fetal demise or intrauterine growth retardation.

    Title Preconceptional Planning.
    Date June 1991
    Journal Obstetrics and Gynecology Clinics of North America
    Excerpt

    Preconceptional counseling has become an important part of obstetrical care. The concept of preconceptional planning is discussed in detail, with an emphasis on particular high-risk groups. The role of genetics and fetal diagnosis is also examined.

    Title Amniotic Fluid Alpha-fetoprotein Levels in the Differential Diagnosis of Cystic Hygroma.
    Date May 1991
    Journal Fetal Therapy
    Excerpt

    In 7 second trimester pregnancies ultrasound (US) demonstrated cystic hygroma colli (CHC); amniocentesis was performed in 6 patients. In the 7th patient, because of oligohydramnios, the fluid for karyotype was aspirated from the CHC. Five pregnancies had been referred secondary to abnormalities on US and 2 others because of low maternal serum alpha-fetoprotein (MSAFP). Four karyotypes were abnormal (45,X;47,XX+21; 47,XY+21; 46,XX/45,X), and 3 had normal karyotypes. Amniotic fluid alpha-fetoprotein (AFAFP) was normal in 4 pregnancies and low in 2 (0.09 MOM, 0.41 MOM). Of 2 pregnancies with trisomy 21 one had been referred for low MSAFP. In 2 pregnancies with normal karyotypes, US findings at early gestational age (14-17 weeks) of small, nonseptated, bilateral CHC disappeared during pregnancy; these women delivered normal, term babies. Most prenatally diagnosed CHC are not in fetuses with Turner syndrome. With a normal karyotype and CHC as the only finding on early US in utero, normal neonatal survival is possible. AFAFP is not elevated in pregnancies with CHC. If AFAFP is elevated with a positive acetylcholinesterase, such results may suggest that the CHC was inadvertently aspirated.

    Title Sequential Invasive Assessment of Fetal Renal Function and the Intrauterine Treatment of Fetal Obstructive Uropathies.
    Date April 1991
    Journal Obstetrics and Gynecology
    Excerpt

    Persistent fetal lower urinary tract obstruction carries a very poor prognosis secondary to damaged renal capacity and oligohydramnios, with its related pulmonary hypoplasia. Several attempts in the past several years to divert urinary flow via an intrauterine shunt have generally been disappointing, primarily because of poor patient selection. In this study we report our experiences with aggressive decompression of megacystis in 11 patients, the value in selected cases of sequential evaluations of fetal urine biochemistry, and the success of intrauterine bladder shunting procedures in appropriately chosen patients. Our data suggest that a single fetal urine determination may be insufficient to declare irreversible damage. Following decompression, improvement in urine biochemistry or its lack may be more likely representative of ultimate outcome. Decompression by either needle aspiration or intrauterine shunting is warranted in carefully selected cases and can save fetuses that are otherwise very likely doomed.

    Title Symmetrical Intrauterine Growth Retardation is Not Symmetrical: Organ-specific Gravimetric Deficits in Midtrimester and Neonatal Trisomy 18.
    Date February 1991
    Journal Fetal Therapy
    Excerpt

    Models to predict normal fetal growth have been of limited accuracy. Abnormal growth is even more problematic. We have developed a mathematical modeling system based on observed body and brain weights to study fetal growth patterns in midgestational trisomy 18 fetuses. Third-degree polynomial-based analysis using observed fetal body and brain weights to generate predicted weights for various organ systems allows for the comparative study of growth patterns at various fetal weights and gestational ages. Our data suggest that what has been previously called symmetrical intrauterine growth retardation associated with aneuploid fetuses is really an asymmetrical pattern that is dynamic in nature and may change through the course of pregnancy.

    Title Determinants of Parental Decisions to Abort for Chromosome Abnormalities.
    Date February 1991
    Journal Prenatal Diagnosis
    Excerpt

    Parental decisions concerning the continuation of pregnancy following prenatal detection of abnormal chromosomes were evaluated for 80 patients whose diagnosis and prenatal counselling were performed in our centre. Twenty-two anomalies were diagnosed by chorionic villus sampling (CVS) and 58 by amniocentesis. The severity of the chromosome anomaly and associated ultrasound findings in the first vs. second trimester were correlated with patients' decisions. No difference was found in the likelihood of parental decisions to interrupt or continue a pregnancy between CVS and amniocentesis for either the 'severe' or the 'questionable' group of chromosome anomalies. Ninety-three per cent of patients with severe prognosis and 27 per cent with questionable prognosis opted for pregnancy termination (p less than 0.0001). The association of ultrasound anomalies and termination was highly significant (p less than 0.001). The severity of the chromosome anomaly, and, to a lesser extent, the visualization of anomalies on ultrasound were the major determinants of parental decisions to terminate the pregnancy. The diagnosis of an anomaly in the first trimester was no more likely ito lead to a termination of pregnancy than in the second trimester.

    Title Beta-lactam-resistant Enterobacter Bacteremia in Febrile Neutropenic Patients Receiving Monotherapy.
    Date October 1990
    Journal The Journal of Infectious Diseases
    Excerpt

    Bacteremia with resistant Enterobacter species has been reported in febrile, neutropenic cancer patients receiving beta-lactam antibiotics. To assess the relationship between enterobacter bacteremia and ceftazidime monotherapy, medical records were reviewed and isolates were tested from 16 neutropenic and 35 nonneutropenic patients with Enterobacter bacteremia. Fifteen isolates from the neutropenic patients were resistant to extended spectrum cephalosporins; only 12 of 35 isolates from the nonneutropenic patients were resistant to Enterobacter species. The neutropenic patients also had more beta-lactam therapy, both immediately before bacteremia and in the preceding year, than did nonneutropenic patients. Prior beta-lactam antibiotic exposure may predispose neutropenic patients to develop resistant Enterobacter bacteremia.

    Title Perinatal Characteristics of the Phenotypically and Chromosomally Abnormal Live-born.
    Date September 1990
    Journal Obstetrics and Gynecology
    Excerpt

    Perinatal characteristics of 105 singleton live infants born during the last 5 years and suspected phenotypically of having karyotypic abnormalities were studied; 33 abnormal karyotypes were found. These pregnancies were compared with all pregnancies delivering at our hospital during the same time period. A retrospective analysis using our perinatal data base examined maternal age, gravidity, parity, race, mode of delivery, birth weight, gestational age at delivery, Apgar scores, and size for gestational age. Within the phenotypically abnormal group, karyotypically normal and abnormal infants showed no significant differences in primary cesarean rates, low Apgar scores, mean birth weight, or appropriateness of size for gestational age. Karyotypically abnormal infants were smaller than the general population (P less than .001) and had lower Apgar scores (P less than .05) but were just as likely to be full-term (66.7 versus 70.3%). These chromosomally abnormal pregnancies had a higher primary cesarean rate than the general population (30.3 versus 15.4%; P less than .001). Black infants undergoing genetic studies had a 37% rate of karyotypic abnormalities, which was significantly higher than the 12.5% rate in the white infants tested (P less than .05). The term black infant with phenotypic abnormalities suggestive of karyotypic abnormalities may be less likely to be recognized and appropriately tested. Increased awareness of phenotypic abnormalities with subsequent genetic testing seems warranted.

    Title Combined Ultrasonography and Amniocentesis for Pregnant Women with Elevated Serum Alpha-fetoprotein. Revising the Risk Estimate.
    Date July 1990
    Journal The Journal of Reproductive Medicine
    Excerpt

    A combination of ultrasound and amniocentesis for alpha-fetoprotein (AFP) and acetylcholinesterase (ACHE) identified 36 anomalous fetuses among 331 pregnant women evaluated at our center for "true" elevated maternal serum alpha-fetoprotein (MSAFP). In six cases the diagnosis of fetal anomalies was missed on initial ultrasonography. In addition, placental pathology was identified in 12 cases and adverse outcome (fetal demise, intrauterine growth retardation, severe oligohydramnios) in 15. When grouped by multiples of the median (MOM), a significant linear correlation was observed between increasing MSAFP and the rate of fetal anomalies or adverse outcome. The frequency of fetal anomalies increased from 0.93% when MSAFP was less than 3.0 MOM to 56% when MSAFP was greater than 7.5 MOM. No differences were observed in the frequency of placental pathology between the groups. A normal ultrasound study in these patients will decrease considerably, but not eliminate, the risk estimate for undetected fetal anomalies. From our 83% ultrasound sensitivity we calculate that with MSAFP greater than 3.0 MOM the risk of anomalies despite a reassuring scan is greater than 1% and clearly warrants offering amniocentesis for amniotic fluid AFP and ACHE. Between 2.5 and 3.0 MOM the risk is relatively low. Amniocentesis should be offered routinely to patients with MSAFP greater than 3.0 MOM and normal ultrasonography. In patients with MSAFP of 2.5-2.9 MOM and satisfactory ultrasonography the risk of amniocentesis may outweigh its benefits.

    Title Midtrimester Diagnosis and Anomalies in the Dup(22q) Syndrome: Correlation of Aneuploidy with Low Maternal Serum Alpha-fetoprotein and Oligohydramnios.
    Date June 1990
    Journal American Journal of Medical Genetics
    Excerpt

    We present the first reported case of prenatally diagnosed dup(22q) syndrome in a 20-year-old woman referred for genetic counseling because of a low maternal serum alpha-fetoprotein value. An ultrasound study at 22 weeks demonstrated oligohydramnios, intrauterine growth retardation, multiple facial malformations, and a cardiac defect. Fetal karyotype was 46, XYdup(22)(pter----q13:: q12----qter) by amniocentesis. Necropsy following pregnancy termination confirmed all prenatally delineated anomalies. Comparison is made with the complete and partial proximal dup(22q) syndromes. We emphasize the correlation between aneuploidy and the presence of low maternal serum alpha-fetoprotein, oligohydramnios, and midgestational intrauterine growth retardation.

    Title Malignant External Otitis: Report on Therapy with Ceftazidime and Review of Therapy and Prognosis.
    Date May 1990
    Journal Reviews of Infectious Diseases
    Excerpt

    We report the treatment of 20 patients with malignant external otitis (MEO) since 1980. Ceftazidime was used in 15 patients, with cure achieved in 11 of 12 evaluatable patients. An aminoglycoside and an antipseudomonal penicillin were used in five patients, four of whom were cured. The presentation, radiographic studies, therapy, outcome, and period of follow-up in the 20 patients are reported. The previously reported cases of MEO are also reviewed, with a focus on the changing therapy and prognosis. The frequencies of diabetes mellitus, cranial nerve deficits, and treatment failures in MEO have all declined significantly since 1985 from frequencies in earlier years. We conclude that there has been an overall improvement in the diagnosis and treatment of MEO and that monotherapy with ceftazidime shows promise against this potentially fatal pseudomonal infection.

    Title Exposure to Bright Light and Darkness to Treat Physiologic Maladaptation to Night Work.
    Date May 1990
    Journal The New England Journal of Medicine
    Excerpt

    Working at night results in a misalignment between the sleep-wake cycle and the output of the hypothalamic pacemaker that regulates the circadian rhythms of certain physiologic and behavioral variables. We evaluated whether such physiologic maladaptation to nighttime work could be prevented effectively by a treatment regimen of exposure to bright light during the night and darkness during the day. We assessed the functioning of the circadian pacemaker in five control and five treatment studies in order to assess the extent of adaptation in eight normal young men to a week of night work. In the control studies, on the sixth consecutive night of sedentary work in ordinary light (approximately 150 lux), the mean (+/- SEM) nadir of the endogenous temperature cycle continued to occur during the night (at 3:31 +/- 0:56 hours), indicating a lack of circadian adaptation to the nighttime work schedule. In contrast, the subjects in the treatment studies were exposed to bright light (7000 to 12,000 lux) at night and to nearly complete darkness during the day, and the temperature nadir shifted after four days of treatment to a significantly later, midafternoon hour (14:53 +/- 0:32; P less than 0.0001), indicating a successful circadian adaptation to daytime sleep and nighttime work. There were concomitant shifts in the 24-hour patterns of plasma cortisol concentration, urinary excretion rate, subjective assessment of alertness, and cognitive performance in the treatment studies. These shifts resulted in a significant improvement in both alertness and cognitive performance in the treatment group during the night-shift hours. We conclude that maladaptation of the human circadian system to night work, with its associated decline in alertness, performance, and quality of daytime sleep, can be treated effectively with scheduled exposure to bright light at night and darkness during the day.

    Title Group A Beta-hemolytic Streptococcal Bacteremia and Hiv Infection.
    Date March 1990
    Journal Southern Medical Journal
    Excerpt

    We describe a case of group A beta-hemolytic streptococcal bacteremia in an individual infected with the human immunodeficiency virus (HIV). The organism was also recovered from the stool, but not from the throat. A review of 19 cases of group A beta-hemolytic streptococcal bacteremia shows an association between an underlying immunologic defect and the occurrence of serious group A beta-hemolytic streptococcal infection in adults. We review evidence in the literature suggesting that there is a predisposition to infection caused by pyogenic bacteria in HIV-infected individuals.

    Title Metabolic Control of Von Gierke Disease (glycogen Storage Disease Type Ia) in Pregnancy: Maintenance of Euglycemia with Cornstarch.
    Date March 1990
    Journal Obstetrics and Gynecology
    Excerpt

    In patients with glycogen storage disease type Ia, glucose-6-phosphatase deficiency reduces the liver's ability to generate free glucose from glycogen. Without a continuous, exogenous source of glucose, severe hypoglycemia and subsequent metabolic perturbations occur. Our observations of a patient with glycogen storage disease type Ia, who also had a clomiphene-induced triplet gestation, suggest that cornstarch, which can be catabolized by debranching enzymes, may be used to maintain a constant state of maternal and fetal euglycemia and correct many metabolic abnormalities. Our data suggest that patients with glycogen storage disease type Ia can be safely managed in pregnancy under a tightly monitored and regulated protocol of raw cornstarch feedings.

    Title Prenatal Genetic Diagnosis Following Recurrent Early Pregnancy Loss.
    Date March 1990
    Journal Obstetrics and Gynecology
    Excerpt

    Recurrent pregnancy loss affects 1% of patients, an incidence higher than expected from the prevalence of spontaneous abortion in the general population. Some couples may show a tendency for aneuploid conceptions. Genetic counseling and amniocentesis or chorionic villus sampling were offered to 305 couples with a history of two or more pregnancy losses and normal parental karyotypes, with no additional known risk factors for aneuploidy. Prenatal diagnostic procedures were performed in 96 pregnancies. Two hundred nine couples declined active intervention, and these pregnancies were followed to delivery. Five chromosomal abnormalities (1.6%) were diagnosed in the study group. A group of 979 prenatal diagnostic procedures performed in "low-risk" pregnancies in Hutzel Hospital was used as controls, and three chromosomal anomalies (0.3%) were diagnosed. That the rate of aneuploid conceptions was statistically significantly (P = .02) higher in low-risk couples experiencing recurrent pregnancy loss than in controls points to a tendency for chromosomal aberrations in their offspring and suggests a place for prenatal diagnosis in subsequent pregnancies.

    Title Nonneurotoxic Tetralin and Indan Analogues of 3,4-(methylenedioxy)amphetamine (mda).
    Date March 1990
    Journal Journal of Medicinal Chemistry
    Excerpt

    Four cyclic analogues of the psychoactive phenethylamine derivative 3,4-(methylenedioxy)amphetamine were studied. These congeners, 5,6- and 4,5-(methylenedioxy)-2-aminoindan (3a and 4a, respectively), and 6,7- and 5,6-(methylenedioxy)-2-aminotetralin (3b and 4b, respectively) were tested for stimulus generalization in the two-lever drug-discrimination paradigm. Two groups of rats were trained to discriminate either LSD tartrate (0.08 mg/kg) from saline, or (+/-)-MDMA.HCl (1.75 mg/kg) from saline. In addition, a 2-aminoindan (5a) and 2-aminotetralin (5b) congener of the hallucinogenic amphetamine 1-(2,5-dimethoxy-4- methylphenyl)-2-aminopropane (DOM) were also evaluated. None of the methylenedioxy compounds substituted in LSD-trained rats, while both 3a and 3b fully substituted in MDMA-trained rats. Compounds 4a and 4b did not substitute in MDMA-trained rats. Compounds 5a and 5b did not substitute in MDMA-trained rats, although 5a substituted in LSD-trained rats, but with relatively low potency compared to its open-chain counterpart. In view of the now well-established serotonin neurotoxicity of 3,4-(methylenedioxy)amphetamine and its N-methyl homologue 1, 3a and 3b were evaluated and compared to 1 for similar toxic effects following a single acute dose of 40 mg/kg sc. Sacrifice at 1 week showed that neither 3a nor 3b depressed rat cortical or hippocampal 5-HT or 5-HIAA levels nor were the number of binding sites (Bmax) depressed for [3H]paroxetine. By contrast, and in agreement with other reports, 1 significantly depressed all three indices of neurotoxicity. These results indicate that 3a and 3b have acute behavioral pharmacology similar to 1 but that they lack similar serotonin neurotoxicity.

    Title The Androgen Receptor of the Testicular-feminized (tfm) Mutant Mouse is Smaller Than the Wild-type Receptor.
    Date March 1989
    Journal Endocrinology
    Excerpt

    The physicochemical and immunological properties of androgen receptors from kidney and brain of testicular-feminized (Tfm) mutant mice and wild-type mice were compared. Analysis by gel filtration and sucrose density gradients revealed that the mol wt of the mutant receptor was 66K (38A; 3.8S) which was significantly smaller than the 110K (53A; 4.6S) size of the wild-type androgen receptor (P less than 0.05). Mixing experiments failed to demonstrate any role for differential proteolysis in the size differences between these receptors. Interaction of the mutant androgen receptor with specific polyclonal antiandrogen receptor antibodies produced significantly smaller immune complexes than that formed with wild-type receptor (12S vs. 17S; P less than 0.01). This confirmed the smaller size of the Tfm mutant androgen receptor and suggested that it contained fewer epitopes. The Tfm kidney cytosols also demonstrated a decreased concentration of androgen receptor-binding activity relative to that of the wild type. Together, these results suggest that the androgen insensitivity associated with the Tfm phenotype is due to a deficiency of androgen receptor in target tissues and a qualitative defect in the androgen receptor protein itself.

    Title Teacher Needs Assessment for the Educational Management of Children with Chronic Illnesses.
    Date February 1989
    Journal The Journal of School Health
    Excerpt

    Three hundred forty-one North Carolina public school teachers were surveyed to determine frequency of teacher contacts with children with chronic health conditions and teachers' needs related to educational management of these children. More than 76% of respondents had taught children with chronic health conditions sometime during their career; 38% reported they had academic coursework related to chronic health conditions, and only 7% indicated their certification requirements were adequate. Parents were identified as the most important source of information about a child's health condition, while in-school resources were reported to be less available and often less helpful. Teachers identified several critical issues in educational management of children with teacher knowledge and preparation about health conditions as the most important concern. Findings indicate a need for more teacher preparation and improved resources for teachers.

    Title Monoclonal Antibodies Against the Androgen Receptor: Recognition of Human and Other Mammalian Androgen Receptors.
    Date July 1988
    Journal Endocrinology
    Excerpt

    Monoclonal antibodies against the androgen receptor (AR) will provide useful probes for elucidating both the structure and function of this important regulatory protein. Recently, human autoimmune anti-AR sera have been described. The purpose of the current work was to immortalize lymphocytes from the blood of patients with high titer anti-AR antibodies and to produce monoclonal antibodies against the receptor in vitro. Human serum samples (10 microliters) were incubated in high ionic strength buffer (400 mM KCl) for 16 h at 0 C with [3H]Mibolerone-labeled cytosol (100-200 fmol AR) from Dunning tumors. Receptor-antibody complexes were precipitated with goat antihuman immunoglobulin (Ig) antibody. From our 1005 serum samples examined, 5 specimens were detected which precipitated greater than 40% of the AR. These antibodies recognized the AR from human, rat, mouse, dog, steer, chicken, and hamster, but did not recognize estrogen, progesterone, or glucocorticoid receptors. By sucrose gradient analysis in high salt (0.4 M KCl) 1 of the antisera shifted the 4.4S monomeric receptor to 8S, and the others shifted the receptor to 18S. However, all of the antibodies were shown to be IgG class by immunoprecipitation with class-specific second antibodies. Peripheral blood lymphocytes donated by these patients were isolated by histopaque density gradient sedimentation, activated in vitro, transformed with Epstein-Barr virus, and seeded into 96-well plates. From 263 million human lymphocytes plated in 96-well dishes, 1215 wells gave rise to Epstein-Barr virus-transformed lymphoblastoid cells, and 8 of these wells were determined to be anti-AR positive. Cells from 2 of the positive wells were cloned and designated CB54 and UA67, both of which secreted IgG class antibodies against the AR. These 2 monoclonal antibodies have been shown to be highly specific for the AR and to cross-react with the AR from human, rat, and hamster. Studies with the monomeric form of the AR and its proteolytic fragment using sucrose density gradients have suggested that the 2 antibodies recognize different epitopes on the monomeric AR molecule. Furthermore, by Western blot analysis the antibodies have identified the AR as an 118K protein on a sodium dodecyl sulfate gel, which is consistent with our previous findings of the mol wt of the AR.

    Title Factors Related to School Absence Among Children with Cardiac Conditions.
    Date December 1987
    Journal American Journal of Diseases of Children (1960)
    Excerpt

    This study compared psychosocial and health factors related to school absence among 62 children with cardiac disease and 62 age-, sex-, and race-matched peers without chronic health conditions. Parents of children with cardiac conditions perceived their children as more vulnerable and rated themselves and their children as having less control over improving their children's health status than did parents of the well children. Increased school absentee rates for the cardiac group were associated with measures of illness severity, parental patterns of absenting their child from school for minor illnesses, and decreased belief in their child's ability to improve his or her health status. For the well comparison group, increased absence was related to external health locus of control beliefs, increased maternal sick days, and demographic factors. School absence was not significantly related to social adaptation, self-esteem, or school achievement for either the well or cardiac groups.

    Title A Common Molecular Weight of the Androgen Receptor Monomer in Different Target Tissues.
    Date September 1987
    Journal Biochemistry
    Excerpt

    Previously reported molecular weights for the monomeric steroid binding subunit of the androgen receptor protein have ranged from 25,000 to 167,000. The molecular weight appeared to vary among different species and target organs, as well as between different investigators. This study has examined androgen receptors from a diverse group of organs and species to determine whether these tissues share a common monomeric form. Gel filtration revealed peaks of specific [3H]dihydrotestosterone binding activity corresponding to Stokes radii of 54, 33, and 20 A in cytosols from several tissues. Phosphocellulose chromatography diminished the appearance of the smaller androgen receptor forms and facilitated the appearance of the larger 54-A form. Mixing experiments suggested that phosphocellulose was stabilizing the 54-A form by binding putative proteases which cleave this larger form. Methods were developed to generate homogenous preparations of a given androgen receptor size for comparative study. Sucrose density gradient analysis showed sedimentation coefficients of 4.5-5.0, 3.5-4.0, and 2.5-3.0 S, respectively. The corresponding calculated molecular weights were 109,000-121,000, 52,000-59,000, and 22,000-27,000. Scatchard analysis of each of these androgen receptor forms demonstrated very similar affinity for [3H]dihydrotestosterone (Kd approximately 1 nM), and each form possessed the ability to bind to DNA-cellulose. Extensively purified preparations of androgen receptor from R3327 tumor contained varying amounts of the three receptor forms even though molybdate and phosphocellulose were used to stabilize the androgen receptor protein during purification.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Androgenic Regulation of Luteinizing Hormone Secretion: Relationship to Androgen Binding in Sheep Pituitary.
    Date July 1987
    Journal Biology of Reproduction
    Excerpt

    Castrated ram lambs (wethers) were investigated for sensitivity to androgen feedback and to determine whether this feedback inhibition of luteinizing hormone (LH) was associated with changes in pituitary androgen receptors. Administration of Silastic capsules containing either dihydrotestosterone or testosterone was found to produce dose-dependent inhibitory effects on serum LH levels in wethers. Physiological dosages of these androgens (i.e., those that produce serum levels of dihydrotestosterone [0.24 ng/ml] or testosterone [2.1 ng/ml] similar to those of intact rams) resulted in differential inhibition of serum LH and LH content of the anterior pituitary. Whereas the inhibitory effect of dihydrotestosterone on pituitary LH content was much more dramatic than that seen with testosterone, the high dosage of testosterone also produced a substantial decrease in pituitary LH content. Responses of the pituitary to changes in serum androgen were compared to responses of the seminal vesicle, which served as a control androgen target organ. Androgen levels were positively correlated with seminal vesicle weights, but pituitary weights were unaffected by castration and/or androgen replacement. Treatments with dihydrotestosterone were associated with decreased cytosol androgen binding activity (i.e., receptors) in pituitary and seminal vesicle, suggesting that both of these tissues were sites of androgen action. Although testosterone inhibited serum LH levels, pituitary cytosol androgen receptors were not affected by changes in serum testosterone. We conclude from these data that dihydrotestosterone is a physiological regulator of pituitary LH secretion in the ram and that further study is needed to investigate the complex actions of testosterone and its metabolites on pituitary function.

    Title Properties of an Intermediate-sized Androgen Receptor: Association with Rna.
    Date February 1987
    Journal Biochemistry
    Excerpt

    This study identifies an intermediate-sized androgen receptor and characterizes its relationship with the 9.1S and 4.4S receptor forms. Under low ionic conditions, at 2-4 degrees C, there exists a 9.1S (+/- 0.17) (n = 30) oligomeric form which does not bind to DNA. Under high ionic conditions, this form dissociates to a 4.4S (+/- 0.08) (n = 18) monomeric form. When the salt concentration is lowered, the 4.4S monomer converts to a species with an intermediate sedimentation coefficient of 7.7S (+/- 0.15) (n = 17) which binds to DNA. Unlike the 9.1S oligomer the 7.7S form is not maintained by sodium molybdate under high ionic conditions but rather dissociates to the 4.4S monomer. To determine whether these forms were associated with RNA, the 7.7S form was incubated with RNase A and analyzed by density gradient centrifugation. The 7.7S form was digested fully by RNase to the 4.4S monomer. The 7.7S form demonstrated a buoyant density of 1.2459 +/- 0.014 g/cm3 (n = 6) in metrizamide gradients, suggesting a ribonucleoprotein component. The sedimentation coefficient of the 9.1S form was unaffected by RNase. These data suggest that the intermediate 7.7S receptor form is composed of 4.4S monomer associated with a ribonucleoprotein molecule(s).

    Title Characterization of Steroid Receptors in Human Prostate Using Mibolerone.
    Date May 1986
    Journal The Prostate
    Excerpt

    Accurate quantitation of androgen receptors requires a radioactive ligand which has affinity and specificity for the receptor and which is stable to metabolic enzymes. In this report, we have characterized the properties of 7 alpha,17 alpha-dimethyl-17 beta-hydroxy-4-estren-3-one (mibolerone) in human benign hyperplastic prostate cytosol and compared them to those of 17 beta-hydroxy-17 alpha-methyl-estra-4,9,11-trien-3-one (R1881). Mibolerone was found to have an affinity (Kd = 1.5 nM) greater than R1881. (Kd = 2.3 nM) for the androgen receptor in human prostate tissue. Surprisingly, mibolerone was found to bind with high affinity to the progesterone receptor in both human prostate (Kd = 5.9 nM) and rabbit uterus (Kd = 1.1 nM). However, binding to this receptor in both species could be blocked with a 500-fold excess of triamcinolone acetonide. [3H]Mibolerone binding to the androgen receptor was competed effectively with unlabeled dihydrotestosterone, R1881, and mibolerone but not by progesterone, diethylstilbestrol or R5020, in the presence of triamcinolone acetonide. Interestingly, mibolerone was more resistant to metabolism than R1881 in prostate cytosol when exposed to elevated temperatures (30 degrees C) for extended periods of time. However, when exposed to high-intensity ultraviolet irradiation, both compounds lost 50% of their binding ability in about 30 minutes. Mibolerone was found to have a very low affinity (Ki = 540 nM) for human sex steroid binding protein. These studies demonstrate that mibolerone is a useful ligand for androgen receptor assays. They also emphasize the need for including competitors of progesterone receptor binding in assays utilizing this steroid for androgen receptor measurements.

    Title Characterization of the Heterogeneity of R3327 Rat Prostatic Tumors Derived from Single-cell Clones.
    Date March 1986
    Journal The Prostate
    Excerpt

    Prostatic adenocarcinoma is characterized by cellular diversity, which is well demonstrated in the Dunning R3327 rat prostatic adenocarcinoma. This heterogeneity may arise from epigenetic influences, ie, cellular adaptation or selection, and/or from genetic changes. To investigate the question of genetic instability, four tissue culture cell lines were derived from single cells isolated from the uncloned late (UCL) passage of the Dunning R3327H prostate cell culture. Each of these clonally derived tissue cultures was injected into castrated and intact young adult male rats for tumor production. Uncloned early (UCE) and UCL passage tissue cultures were also propagated as solid tumors. Tumors and the cultures from which they were derived were examined for evidence of phenotypic and genetic changes using morphological and cytometric methods. Transmission and scanning electron microscopy revealed only slight differences among the cell cultures. A single population of diploid cells was demonstrated in each of the cell cultures by propidium iodide staining and subsequent flow cytometric measurement of DNA content/nucleus. Tumors of unicellular as well as multicellular origin exhibited extreme heterogeneity of histological features, both among animals as well as within a single tumor. Tumors were surveyed and tissue types were characterized and cataloged. Clone 3 was generally better differentiated than the others; tumors from castrated animals were better differentiated than those from intact animals. Flow cytometry revealed multiple hyperdiploid cell populations that were variable from one sample to another. We concluded that changes in genotype as well as phenotype occurred in the tumors derived from single cells. Some of these changes may have occurred in the cells while still in culture.

    Title Differential Effects of Prolactin on Rat Dorsolateral Prostate and R3327 Prostatic Tumor Sublines.
    Date July 1985
    Journal The Journal of Urology
    Excerpt

    Many investigators have reported effects of the pituitary hormone, prolactin, on the physiology and biochemistry of the rat prostate gland, particularly the lateral or dorsolateral lobe. The Dunning R3327H is a transplantable rat prostatic adenocarcinoma derived from a spontaneous tumor of the Copenhagen rat dorsolateral prostate. This study describes and compares morphological and physiological effects of prolactin on rat dorsolateral prostate and two sublines of the Dunning tumor. Ectopic pituitary grafts were used to induce chronic hyperprolactinemia in castrated rats receiving androgen supplement to provide a relatively controlled hormonal environment in which the effects of prolactin were maximally and consistently observed. Gravimetric and biochemical analyses, as well as ultrastructural study, provided evidence of prolactin's stimulatory effect on dorsolateral prostate growth and secretory activity. Hyperprolactinemia stimulated the growth of the well-differentiated, androgen-dependent R3327/3219 tumor subline with an increase in weight, volume and the total content of DNA, protein and zinc. There were no changes in tumor morphology. In contrast, the anaplastic androgen-independent R3327/150 tumor subline did not respond to graft-induced hyperprolactinemia. This differential response of the two R3327 tumor sublines attests to the complexity of prolactin's effects on prostatic tissue and to the extent of the deterioration of endocrine control that often accompanies tumor progression. Prolactin binding in the R3327 sublines was studied using immunohistochemical staining and radioligand assay, but produced complex results which raise questions about the discrepancy between hormone binding and biological action of prolactin in prostatic tissues.

    Title School Achievement and Absence in Children with Chronic Health Conditions.
    Date May 1985
    Journal The Journal of Pediatrics
    Excerpt

    Families of 270 children with chronic health conditions observed in 11 subspecialty clinics at a tertiary care center were surveyed to assess the relation of demographic and health variables to school achievement and absenteeism. National achievement test scores and school days absent were compared with North Carolina state results. The mean days absent for children with chronic health conditions was 16 days, compared with the state average of less than 7 days, during the 1981-1982 academic year. The mean national achievement score for the chronically ill children was at the 51st percentile, compared with the 63rd percentile for the state's sixth graders. Log of school days absent was correlated with the number of clinic visits, physician rating of activity limitations, sex, and specific health conditions (R2 = 0.17, P = 0.001). National achievement scores were mainly related to socioeconomic factors and specific health conditions (R2 = 0.44, P = 0.001), but were unrelated to school absence. Children with spina bifida, sickle cell disease, or epilepsy, and children with the added burden of low socioeconomic status, were at particular risk for poor school achievement.

    Title Nerve Growth Cones Isolated from Fetal Rat Brain: Subcellular Fractionation and Characterization.
    Date February 1984
    Journal Cell
    Excerpt

    The biochemical and functional characterization of the nerve growth cone is of major interest for studies on mechanisms involved in nervous system development. We describe the isolation from fetal brain of membrane-bound fragments of nerve growth cones by density gradient fractionation. These so-called growth cone particles are highly uniform and identifiable on the basis of their organelle complement. Furthermore, they co-purify in mixing experiments with fragments of radiolabeled and light microscopically identified nerve growth cones from primary cultures. The possibility of isolating growth cone fragments in quantity renders feasible the analysis of molecular mechanisms involved in growth cone function.

    Title Immunopathologic Study of Minimal Change Glomerular Disease with Mesangial Igm Deposits.
    Date October 1981
    Journal Nephron
    Excerpt

    Renal biopsies from 21 patients with minimal change nephrotic syndrome and mesangial IgM deposits were investigated by means of fluorescence, light and electron microscopy; elution of tissue-bound antibody; and fixation of heterologous (guinea pig) complement. In 12 patients complement and IgM deposits were associated and, in 4 of these, electron dense deposits conforming to immune complexes were detected in mesangia. Antibody elution and heterologous complement fixation studies in tissues suggested that such immune reactants may represent interaction of complement-fixing antibody and antigen. Long-term follow-up studies are needed to determine the clinical relevance of IgM deposits in minimal change nephrotic syndrome.

    Title Cheetahs of the Deep Sea: Deep Foraging Sprints in Short-finned Pilot Whales off Tenerife (canary Islands).
    Date
    Journal The Journal of Animal Ecology
    Excerpt

    1. Empirical testing of optimal foraging models for breath-hold divers has been difficult. Here we report data from sound and movement recording DTags placed on 23 short-finned pilot whales off Tenerife to study the foraging strategies used to catch deep-water prey. 2. Day and night foraging dives had a maximum depth and duration of 1018 m and 21 min. Vocal behaviour during dives was consistent with biosonar-based foraging, with long series of echolocation clicks interspersed with buzzes. Similar buzzes have been associated with prey capture attempts in other echolocating species. 3. Foraging dives seemed to adapt to circadian rhythms. Deep dives during the day were deeper, but contained fewer buzzes (median 1), than night-time deep dives (median 5 buzzes). 4. In most deep (540-1019 m) daytime dives with buzzes, a downward directed sprint reaching up to 9 m s(-1) occurred just prior to a buzz and coincided with the deepest point in the dive, suggestive of a chase after escaping prey. 5. A large percentage (10-36%) of the drag-related locomotion cost of these dives (15 min long) is spent in sprinting (19-79 s). This energetic foraging tactic focused on a single or few prey items has not been observed previously in deep-diving mammals but resembles the high-risk/high-gain strategy of some terrestrial hunters such as cheetahs. 6. Deep sprints contrast with the expectation that deep-diving mammals will swim at moderate speeds optimized to reduce oxygen consumption and maximize foraging time at depth. Pilot whales may have developed this tactic to target a deep-water niche formed by large/calorific/fast moving prey such as giant squid.

    Title Prenatal Course and Postnatal Management of Peripheral Bronchial Atresia: Association with Congenital Cystic Adenomatoid Malformation of the Lung.
    Date
    Journal Fetal Diagnosis and Therapy
    Excerpt

    OBJECTIVE: Peripheral bronchial atresia (PBA), a newly identified fetal lung lesion, is often asymptomatic and managed nonoperatively. However, recent studies suggest that bronchial atresia plays a role in the etiology of microcystic maldevelopment present in congenital cystic adenomatoid malformations (CCAM) which require resection to decrease the risk of infection, pneumothorax and malignant degeneration. The purpose of this study was to evaluate the prenatal radiographic and postnatal computed tomography (CT) scan/pathology findings with attention to the pathologic diagnosis of microcystic maldevelopment in infants with the presumptive diagnosis of PBA. METHODS: A retrospective review of prenatal and postnatal records of patients diagnosed with fetal lung lesions was performed. Two groups of patients were identified: (1) patients diagnosed with PBA on postnatal CT scan (n = 16), and (2) patients with the pathologically confirmed diagnosis of PBA independent of postnatal CT findings (n = 23). RESULTS: Prenatal ultrasound diagnosis of these lesions included CCAMs, hybrid lesions, bronchopulmonary sequestrations and bronchial atresia. Eleven of the 16 patients in group 1 with the postnatal radiologic diagnosis of PBA underwent surgical resection, 6 of which were found to have microcystic changes consistent with CCAM. Evaluation of the 23 patients in group 2 with pathologically confirmed PBA identified 65% that had evidence of microcystic maldevelopment consistent with the small cyst type of CCAM. CONCLUSION: Radiographically diagnosed PBA as well as pathologically confirmed PBA is frequently associated with microcystic changes consistent with the small cyst type of CCAM. Thus, operative management should be considered for PBA to decrease CCAM-associated risks.

    Title Association Between the Candidate Susceptibility Gene Acvr2a on Chromosome 2q22 and Pre-eclampsia in a Large Norwegian Population-based Study (the Hunt Study).
    Date
    Journal European Journal of Human Genetics : Ejhg
    Excerpt

    Genome-wide scans in Icelandic, Australian/New Zealand and Finnish pedigrees have provided evidence for maternal susceptibility loci for pre-eclampsia on chromosome 2, although at different positions (Iceland: 2p13 and 2q23, Australia/New Zealand: 2p11-12 and 2q22, Finland: 2p25). In this project, a large population-based (n=65 000) nested case-control study was performed in Norway to further explore the association between positional candidate genes on chromosome 2q and pre-eclampsia, using single-nucleotide polymorphisms (SNPs). DNA samples from 1139 cases (women with one or more pre-eclamptic pregnancies) and 2269 controls (women with normal pregnancies) were genotyped using the Applied Biosystems SNPlex high-throughput genotyping assay. In total, 71 SNPs within positional candidate genes at 2q22-23 locus on chromosome 2 were genotyped in each individual. Genotype data were statistically analysed with the sequential oligogenic linkage analysis routines (SOLAR) computer package. Nominal evidence of association was found for six SNPs (rs1014064, rs17742134, rs1424941, rs2161983, rs3768687 and rs3764955) within the activin receptor type 2 gene (ACVR2A) (all P-values <0.05). The non-independence of statistical tests due to linkage disequilibrium between SNPs at a false discovery rate of 5% identifies our four best SNPs (rs1424941, rs1014064, rs2161983 and rs3768687) to remain statistically significant. The fact that populations with different ancestors (Iceland/Norway-Australia/New Zealand) demonstrate a common maternal pre-eclampsia susceptibility locus on chromosome 2q22-23, may suggest a general role of this locus, and possibly the ACVR2A gene, in pre-eclampsia pathogenesis.European Journal of Human Genetics advance online publication, 10 September 2008; doi:10.1038/ejhg.2008.158.

    Title Fetal Tracheal Occlusion for Severe Congenital Diaphragmatic Hernia in Humans: a Morphometric Study of Lung Parenchyma and Muscularization of Pulmonary Arterioles.
    Date
    Journal Journal of Pediatric Surgery
    Excerpt

    OBJECTIVE: The aim of this study is to examine structure of lung parenchyma (Pp) and muscularization of pulmonary arterioles (PAs) in human fetuses that underwent tracheal occlusion (TO) therapy for severe congenital diaphragmatic hernia (CDH). MATERIAL: Fifteen fetuses underwent TO, with 5 survivors (Am J Obstet Gynecol. 2000:183;1059-1066). Paraffin-embedded lung specimens from 7 of 10 nonsurvivors (CDH-TO) and 6 age-matched fetuses (CDH) were available for morphometric analysis, which included measurements of point fraction of lung Pp and surface density. The PAs were categorized according to external diameter (<70 microm and 70 <or= 140 microm). Percent medial wall thickness (%MWT) was calculated by dividing raw measurements of MWT by external diameter. RESULTS: Gestational age at TO was 27.6 +/- 0.9 weeks with a mean duration of TO of 32.6 +/- 6.8 days. Gestational age at delivery (CDH-TO 31.9 +/- 0.9 vs CDH 35.4 +/- 1.8 weeks; P = .18) and postnatal survival time (CDH-TO 20.5 +/- 6.0 vs CDH 18.6 +/- 7.8 days; P = .85) were not significantly different between groups. Tracheal occlusion significantly increased the lung-to-body weight ratio (CDH-TO 13.0 +/- 2.2 vs CDH 6.6 +/- 0.9; P = .02). Tracheal occlusion tended to decrease right-lung Pp (CDH-TO 54.6% +/- 2.6% vs CDH 65.7% +/- 5.9%; P = .05), whereas left-lung Pp was not different between groups (CDH-TO 63.0% +/- 3.5% vs CDH 66.7% +/- 4.1%; P = .51). Surface density of airspaces was not different between groups in either left (CDH-TO 171.3 +/- 16.1 cm(-1) vs CDH 151.1 +/- 8.1 cm(-1); P = .34) or right (CDH-TO 172.0 +/- 10.6 cm(-1) vs CDH 160.8 +/- 3.6 cm(-1); P = .33) lungs. The %MWT in small and large PA was similar between groups. CONCLUSIONS: Open prenatal TO in human fetuses increased lung growth, as evidenced by an increase in lung weight, but did not improve parenchymal structure or muscularization of PAs.

    Title Utility of Fetal Muscle Biopsy for Diagnosis of Nemaline Myopathy.
    Date
    Journal Fetal Diagnosis and Therapy
    Excerpt

    Objectives: To report and discuss prenatal diagnosis of nemaline myopathy (NM) using fetal muscle biopsy. Methods: A consanguineous couple, with a history of a child with a clinical diagnosis of NM but no molecular genetic confirmation, was referred for prenatal diagnosis in two subsequent pregnancies. Fetal muscle biopsy with ultrasound guidance was undertaken at 22 and 21 weeks, respectively. Results: Immunohistochemical and ultrastructural analysis of the fetal muscle specimen from the first 'at-risk' pregnancy was consistent with a diagnosis of NM and that pregnancy was terminated. Analysis of the fetal muscle specimen from the subsequent pregnancy revealed no pathologic abnormality. The pregnancy continued, and the child is unaffected. Conclusion: This represents the first reported prenatal diagnosis of NM by fetal muscle biopsy. Pathologic changes characteristic of NM can be identified in mid-second trimester fetal muscle.

    Title The Zeaxanthin-independent and Zeaxanthin-dependent Qe Components of Non-photochemical Quenching Involve Common Conformational Changes Within the Photosystem Ii Antenna in Arabidopsis Thaliana.
    Date
    Journal Plant Physiology
    Excerpt

    The light harvesting antenna of higher plant photosystem II (LHCII) has the intrinsic capacity to dissipate excess light energy as heat in a process termed nonphotochemical quenching (NPQ). Recent studies suggest that zeaxanthin and lutein both contribute to the rapidly relaxing component of NPQ, qE, possibly acting respectively in the minor monomeric antenna complexes and the major trimeric LHCII. To distinguish whether zeaxanthin and lutein act independently as quenchers at separate sites, or alternatively whether zeaxanthin fulfils an allosteric role regulating lutein-mediated quenching, the kinetics of qE and the qE-related conformational changes (DeltaA535) were compared in Arabidopsis thaliana mutant/ antisense plants with altered contents of minor antenna (kolhcb6, aslhcb4), trimeric LHCII (aslhcb2), lutein (lut2, lut2npq1, lut2npq2) and zeaxanthin (npq1, npq2). The kinetics of the two components of NPQ induction arising from zeaxanthin-independent and zeaxanthin-dependent qE were both sensitive to changes in the protein composition of the PSII antenna. The replacement of lutein by zeaxanthin or violaxanthin in the internal Lhcb protein binding sites affected the kinetics and relative amplitude of each component, as well as the absolute chlorophyll fluorescence lifetime. Both components of qE were characterized by a conformational change leading to nearly identical absorption changes in the Soret region that indicated the involvement of the LHCII lutein 1 domain. Based on these observations we suggest that both components of qE arise from a common quenching mechanism based upon a conformational change within the PSII antenna, optimized by Lhcb subunit-subunit interactions and tuned by the synergistic effects of external and internally bound xanthophylls.

    Title Intradural Inclusion Cysts Following in Utero Closure of Myelomeningocele: Clinical Implications and Follow-up Findings.
    Date
    Journal Journal of Neurosurgery. Pediatrics
    Excerpt

    Object The goal in this study was to evaluate the incidence and clinical implications of the development of cutaneously derived intradural inclusion cysts (ICs) following fetal myelomeningocele (fMMC) closure. Methods Retrospective databases and responses to a parental questionnaire were reviewed to determine the incidence, clinical presentation, and outcomes of fMMCs in children in whom ICs developed at follow-up. Results Prior to the National Institutes of Health (NIH)-sponsored Management of Myelomeningocele Study (MOMS), 54 patients underwent fMMC closure at the authors' institution. Sixteen (30%) presented with symptomatic tethered cord syndrome (TCS) at a median age of 27 months (range 4-93 months). Ten (63%) of the 16 (19% of the total) developed TCS in association with an intradural IC. In 9 (90%) of 10 patients, the IC was seen on preoperative MR imaging, and in 1 it was found during surgery. Four additional children (7% of the total) with evidence of an IC on surveillance MR imaging are currently asymptomatic at 94, 84, 60, and 60 months of age, respectively. All but 1 (an L-3 level lesion) IC developed in infants with L-4 and L-5 defects. After cyst removal, 6 children are asymptomatic at a median follow-up of 36 months (range 12-63 months). Following IC removal, 4 children lost normal bladder function and now require clean intermittent catheterization, and 1 lost normal leg function and now requires a walking aid for ambulation. Histologically, 8 lesions were dermoid, 1 was an epidermoid, and 1 was a mixed dermoid-epidermoid IC. Three patients developed another IC and required its removal at 24, 39, and 51 months, respectively. One required another tethered cord release within 57 months after IC removal. Conclusions Cutaneously derived intradural ICs can develop following fMMC surgery. Deterioration of bladder function, risk of recurrence, and loss of lower-extremity function appear to be the most important long-term complications of IC in children with fMMCs. The ongoing NIH-sponsored MOMS may help determine whether children with fMMC are at increased risk of IC development compared with children treated with postnatal MMC closure. Parents seeking fMMC closure should be informed about the possibility of IC formation and the potential clinical consequences.

    Title Dynamics of Higher Plant Photosystem Cross-section Associated with State Transitions.
    Date
    Journal Photosynthesis Research
    Excerpt

    Photosynthetic state transitions are a well-known phenomenon of short-term adaptation of the photosynthetic membrane to changes in spectral quality of light in low light environments. The principles of the monitoring and quantification of the process in higher plants are revised here. The use of the low-temperature excitation fluorescence spectroscopy for analysis of the photosystem I antenna cross-section dynamics is described. This cross section was found to increase by 20-25% exclusively due to the migration and attachment of LHCIIb complex in State 2. Analysis of the fine structure of the additional PSI cross-section spectrum revealed the 510 nm band, characteristic of Lutein 2 of LHCIIb and present only when the complex is in a trimeric state. The excitation fluorescence spectrum of the phospho-LHCII resembles the spectrum of aggregated and hence quenched LHCII. This novel observation could explain the fact that at no point in the course of the state transition high fluorescence and long lifetime components of detached trimeric LHCII have ever been observed. In the plants lacking Lhcb1 and 2 proteins and unable to perform state transitions, compensatory sustained adjustments of the photosystem I and II antennae have been revealed. Whilst the major part of the photosystem II antenna is built largely of CP26 trimers, possessing less chlorophyll b and more of the red-shifted chlorophyll a, photosystem I in these plants contains more than 20% of extra LHCI antenna enriched in chlorophyll b. Hence, both photosystems in the plants lacking state transitions have less spectrally distinct antennae, which enable to avoid energy imbalance due to the changes in the light quality. These alterations reveal remarkable plasticity of the higher plant photosynthetic antenna design providing the basis for a flexible adaptation to the light environment.

    Title Passive Acoustic Detection of Deep-diving Beaked Whales.
    Date
    Journal The Journal of the Acoustical Society of America
    Excerpt

    Beaked whales can remain submerged for an hour or more and are difficult to sight when they come to the surface to breathe. Passive acoustic detection (PAD) not only complements traditional visual-based methods for detecting these species but also can be more effective because beaked whales produce clicks regularly to echolocate on prey during deep foraging dives. The effectiveness of PAD for beaked whales depends not only on the acoustic behavior and output of the animals but also on environmental conditions and the quality of the passive sonar implemented. A primary constraint on the range at which beaked whale clicks can be detected involves their high frequencies, which attenuate rapidly, resulting in limited ranges of detection, especially in adverse environmental conditions. Given current knowledge of source parameters and in good conditions, for example, with a wind speed of 2 ms, a receiver close to the surface should be able to detect acoustically Cuvier's beaked whales with a high probability at distances up to 0.7 km, provided the listening duration exceeds the deep dive interval, about 2.5 h on average. Detection ranges beyond 4 km are unlikely and would require low ambient noise or special sound propagation conditions.

    Title Comparative Genomic Analysis Reveals Species-dependent Complexities That Explain Difficulties with Microsatellite Marker Development in Molluscs.
    Date
    Journal Heredity
    Excerpt

    Reliable population DNA molecular markers are difficult to develop for molluscs, the reasons for which are largely unknown. Identical protocols for microsatellite marker development were implemented in three gastropods. Success rates were lower for Gibbula cineraria compared to Littorina littorea and L. saxatilis. Comparative genomic analysis of 47.2 kb of microsatellite containing sequences (MCS) revealed a high incidence of cryptic repetitive DNA in their flanking regions. The majority of these were novel, and could be grouped into DNA families based upon sequence similarities. Significant inter-specific variation in abundance of cryptic repetitive DNA and DNA families was observed. Repbase scans show that a large proportion of cryptic repetitive DNA was identified as transposable elements (TEs). We argue that a large number of TEs and their transpositional activity may be linked to differential rates of DNA multiplication and recombination. This is likely to be an important factor explaining inter-specific variation in genome stability and hence microsatellite marker development success rates. Gastropods also differed significantly in the type of TEs classes (autonomous vs non-autonomous) observed. We propose that dissimilar transpositional mechanisms differentiate the TE classes in terms of their propensity for transposition, fixation and/or silencing. Consequently, the phylogenetic conservation of non-autonomous TEs, such as CvA, suggests that dispersal of these elements may have behaved as microsatellite-inducing elements. Results seem to indicate that, compared to autonomous, non-autonomous TEs maybe have a more active role in genome rearrangement processes. The implications of the findings for genomic rearrangement, stability and marker development are discussed.

    Title Fetal Cardiovascular Effects of Lower Urinary Tract Obstruction with Giant Bladder.
    Date
    Journal Ultrasound in Obstetrics & Gynecology : the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology
    Excerpt

    Lower urinary tract obstruction (LUTO) with massive bladder distension impacts on a variety of developing organ systems with consequent morbidity and mortality. The impact of LUTO on the fetal cardiovascular system has not previously been investigated. We hypothesize that a giant, distended bladder within the pelvis may cause vascular compression with observable consequences.

    Title Stox2 but Not Stox1 is Differentially Expressed in Decidua from Pre-eclamptic Women: Data from the Second Nord-trondelag Health Study.
    Date
    Journal Molecular Human Reproduction
    Excerpt

    Variation in the Storkhead box-1 (STOX1) gene has previously been associated with pre-eclampsia. In this study, we assess candidate single nucleotide polymorphisms (SNPs) in STOX1 in an independent population cohort of pre-eclamptic (n = 1.139) and non-pre-eclamptic (n = 2.269) women (the HUNT2 study). We also compare gene expression levels of STOX1 and its paralogue, Storkhead box-2 (STOX2) in decidual tissue from pregnancies complicated by pre-eclampsia and/or fetal growth restriction (FGR) (n = 40) to expression levels in decidual tissue from uncomplicated pregnancies (n = 59). We cannot confirm association of the candidate SNPs to pre-eclampsia (P > 0.05). For STOX1, no differential gene expression was observed in any of the case groups, whereas STOX2 showed significantly lower expression in deciduas from pregnancies complicated by both pre-eclampsia and FGR as compared with controls (P = 0.01). We further report a strong correlation between transcriptional alterations reported previously in choriocarcinoma cells over expressing STOX1A and alterations observed in decidual tissue of pre-eclamptic women with FGR.

    Title A Theoretical Investigation of the Photophysical Consequences of Major Plant Light-harvesting Complex Aggregation Within the Photosynthetic Membrane.
    Date
    Journal The Journal of Physical Chemistry. B
    Excerpt

    Spectroscopic measurements of Arabidopsis leaves have shown that the energy-dependent component of non-photochemical quenching (NPQ), known as qE, is associated with an absorption change at 535 nm (ΔA(535)). Identical measurements on the zeaxanthin-deficient mutant npq1 reveal a similar spectroscopic signature at 525 nm (ΔA(525)). We investigated whether these red-shifts may arise from excitonic interactions among homodimers of xanthophylls, zeaxanthin, and violaxanthin, bound at the peripheral V1 binding site on adjacent light-harvesting complex II (LHCII) trimers. Estimates of the relative geometries of these pigment pairs were obtained from the structure of LHCII. The excitonic couplings of zeaxanthin and violaxanthin dimers were probed using the time-dependent density functional theory method (TD-DFT). Calculations indicated that dimers formed between zeaxanthin or violaxanthin molecules using the published LHCII structure resulted in absorption blue shifts, typical of an H-type (parallel) geometry. In contrast, if the volume of the LHCII structure was modified to reflect the change in membrane thickness that occurs upon ΔpH formation, then both zeaxanthin and violaxanthin dimers adopted a J-type (collinear) geometry, and the resulting spectral shift was to the red region. The magnitudes of these predicted red-shifts are in good agreement with the experimental magnitudes. We therefore conclude that the observed xanthophyll red-shift results from the combination of both LHCII aggregation and changes in membrane thickness during qE. ΔA(535) may therefore be considered a "marker of aggregation" between LHCII trimers upon qE formation.

    Title Far-red Light-regulated Efficient Energy Transfer from Phycobilisomes to Photosystem I in the Red Microalga Galdieria Sulphuraria and Photosystems-related Heterogeneity of Phycobilisome Population.
    Date
    Journal Biochimica Et Biophysica Acta
    Excerpt

    Phycobilisomes (PBS) are the major photosynthetic antenna complexes in cyanobacteria and red algae. In the red microalga Galdieria sulphuraria, action spectra measured separately for photosynthetic activities of photosystem I (PSI) and photosystem II (PSII) demonstrate that PBS fraction attributed to PSI is more sensitive to stress conditions and upon nitrogen starvation disappears from the cell earlier than the fraction of PBS coupled to PSII. Preillumination of the cells by actinic far-red light primarily absorbed by PSI caused an increase in the amplitude of the PBS low-temperature fluorescence emission that was accompanied by the decrease in PBS region of the PSI 77 K fluorescence excitation spectrum. Under the same conditions, fluorescence excitation spectrum of PSII remained unchanged. The amplitude of P700 photooxidation in PBS-absorbed light at physiological temperature was found to match the fluorescence changes observed at 77 K. The far-red light adaptations were reversible within 2-5min. It is suggested that the short-term fluorescence alterations observed in far-red light are triggered by the redox state of P700 and correspond to the temporal detachment of the PBS antenna from the core complexes of PSI. Furthermore, the absence of any change in the 77 K fluorescence excitation cross-section of PSII suggests that light energy transfer from PBS to PSI in G. sulphuraria is direct and does not occur through PSII. Finally, a novel photoprotective role of PBS in red algae is discussed.

    Title Local Application of the Endocannabinoid Hydrolysis Inhibitor Urb597 Reduces Nociception in Spontaneous and Chemically Induced Models of Osteoarthritis.
    Date
    Journal Pain
    Excerpt

    The present study examined whether enhancement of endogenous cannabinoid levels by administration of the fatty acid amide hydrolase inhibitor URB597 could modulate joint nociception in 2 rodent models of osteoarthritis (OA). OA-like changes were induced in male Wistar rats by intra-articular injection of monoiodoacetate, while Dunkin-Hartley guinea pigs (age 9-12months) develop OA naturally and were used as a model of spontaneous OA. Joint nociception was measured by recording electrophysiologically from knee joint primary afferents in response to noxious hyper-rotation of the joint before and after close intra-arterial injection of URB597 (0.03mg; 0.1mL bolus); the CB(1) receptor antagonist AM251 (1mg/kg intraperitoneally) or the CB(2) receptor antagonist AM630 (1mg/kg intraperitoneally). The effect of systemic URB597 administration (5mg/kg) on joint pain perception in the monoiodoacetate model was determined by hindlimb incapacitance. Peripheral injection of URB597 caused afferent firing rate to be significantly reduced by up to 56% in the rat OA model and by up to 69% in the guinea pig OA model. Systemic co-administration of AM251, but not AM630, abolished the antinociceptive effect of URB597 in both models. URB597 had no effect in saline-injected control rat joints or in nonarthritic guinea pigs. Systemic URB597 administration significantly reduced hindlimb incapacitance in monoiodoacetate joints and co-administration of the CB(1) antagonist abolished this effect. Local injection of URB597 into OA knee joints reduces mechanonociception and pain, and this response is mediated by CB(1) receptors. Targeting endocannabinoid-metabolizing enzymes in the peripheral nervous system could offer novel therapeutic approaches for the treatment of OA pain. Peripheral blockade of endocannabinoid hydrolysis reduced mechanonociception and pain in osteoarthritic knee joints.

    Title Elevated Δph Restores Rapidly Reversible Photoprotective Energy Dissipation in Arabidopsis Chloroplasts Deficient in Lutein and Xanthophyll Cycle Activity.
    Date
    Journal Planta
    Excerpt

    The xanthophylls of the light-harvesting complexes of photosystem II (LHCII), zeaxanthin, and lutein are thought to be essential for non-photochemical quenching (NPQ). NPQ is a process of photoprotective energy dissipation in photosystem II (PSII). The major rapidly reversible component of NPQ, qE, is activated by the transmembrane proton gradient, and involves the quenching of antenna chlorophyll excited states by the xanthophylls lutein and zeaxanthin. Using diaminodurene (DAD), a mediator of cyclic electron flow around photosystem I, to enhance ΔpH we demonstrate that qE can still be formed in the absence of lutein and light-induced formation of zeaxanthin in chloroplasts derived from the normally qE-deficient lut2npq1 mutant of Arabidopsis. The qE induced by high ΔpH in lut2npq1 chloroplasts quenched the level of fluorescence when all PSII reaction centers were in the open state (F (o) state), protected PSII reaction centers from photoinhibition, was sensitive to the uncoupler nigericin, and was accompanied by absorption changes in the 410-565 nm region. Titrations show the ΔpH threshold for activation of qE in lut2npq1 chloroplasts lies outside the normal physiological range and is highly cooperative. Comparison of quenching in isolated trimeric (LHCII) and monomeric (CP26) light-harvesting complexes from lut2npq1 plants revealed a similarly shifted pH dependency compared with wild-type LHCII. The implications for the roles of lutein and zeaxanthin as direct quenchers of excitation energy are discussed. Furthermore, we argue that the control over the proton-antenna association constant, pK, occurs via influence of xanthophyll structure on the interconnected phenomena of light-harvesting antenna reorganization/aggregation and hydrophobicity.

    Title Preschool Neurobehavioral Outcome Following Fetal Myelomeningocele Surgery.
    Date
    Journal Fetal Diagnosis and Therapy
    Excerpt

    It was the aim of this study to assess the prevalence of preschool neurobehavioral problems in children following fetal myelomeningocele (fMMC) surgery.

    Title Light-harvesting Antenna Composition Controls the Macrostructure and Dynamics of Thylakoid Membranes in Arabidopsis.
    Date
    Journal The Plant Journal : for Cell and Molecular Biology
    Excerpt

    We characterized a set of Arabidopsis mutants deficient in specific light-harvesting proteins, using freeze-fracture electron microscopy to probe the organization of complexes in the membrane and confocal fluorescence recovery after photobleaching to probe the dynamics of thylakoid membranes within intact chloroplasts. The same methods were used to characterize mutants lacking or over-expressing PsbS, a protein related to light-harvesting complexes that appears to play a role in regulation of photosynthetic light harvesting. We found that changes in the complement of light-harvesting complexes and PsbS have striking effects on the photosystem II macrostructure, and that these effects correlate with changes in the mobility of chlorophyll proteins within the thylakoid membrane. The mobility of chlorophyll proteins was found to correlate with the extent of photoprotective non-photochemical quenching, consistent with the idea that non-photochemical quenching involves extensive re-organization of complexes in the membrane. We suggest that a key feature of the physiological function of PsbS is to decrease the formation of ordered semi-crystalline arrays of photosystem II in the low-light state. Thus the presence of PsbS leads to an increase in the fluidity of the membrane, accelerating the re-organization of the photosystem II macrostructure that is necessary for induction of non-photochemical quenching.

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